PET CNS Imaging:

PET CNS Imaging:

Normal CNS tracer distribution:

FDG uptake in the brain varies with patient age [71]. Infants typically have a diffusely lower brain glucose metabolism, which is approximately 30% of adult subjects [71]. Subsequently, there is a rapid increase in brain glucose metabolism that begins after 4 months of age and reaches a peak level that is ultimately 30% higher than that of adults by about 4 years of age [71]. The brain glucose metabolic pattern in infants also reflects the functional brain maturation, with the frontal and parietal association cortex demonstrating lower FDG uptake (a pattern similar to Alzheimer disease) and progressively increasing to 1 year of age when the pattern becomes similar to adults [71]. FDG uptake in the brain is usually symmetric in the frontoparietal and occipital regions, but temporal lobe activity is often asymmetric across all age groups with the left temporal lobe being hypometabolic in comparison to the right side [71]. Depression and certain antiepileptic drugs, such as phenobarbital and valproate sodium, have been shown to cause diffusely decreased cerebral metabolic activity and phenytoin can lead to decreased glucose metabolism in the cerebellum [71].

Seizure Disorders:

(For more extensive discussion, see Tc-HMPAO seizure imaging in CNS section)

Epilepsy is one of the most prevalent neurological disorders affecting 0.5-1% of the general population [34,71]. Seizures can be classified as either partial (focal) or generalized. Partial seizures originate in a given area of the brain and can be divided into simple (with no impairment of consciousness) and complex (with impairment of consciousness). Most partial complex seizures originate in the temporal lobe. The majority of patients can be treated effectively with antiepileptic drugs, but up to 20-25% of patients with seizure disorders (and over 40% of patients with complex partial seizures) may be inadequately controlled (intractable epilepsy) [34,71]. Patients unresponsive to anti-convulsant therapy may be candidates for surgical treatment- particularly those with temporal lobe epilepsy- if the patient has a focal epileptogenic abnormality and early surgical resection has been shown to substantially improve prognosis in these patients [71]. Surgery can decrease (in up to 92% of patients) or eliminate (up to 68% of patients) seizure episodes, however, accurate localization of the seizure focus is key for a successful post surgical outcome [34]. Unfortunately scalp EEG often fails to accurately localize the seizure focus. Depth EEG is much more accurate, but it is also extremely invasive (requiring a craniotomy) and suffers from regional under sampling. Extratemporal cortical resections performed for seizure foci in the frontal, parietal, or occipital lobes is less successful and only 40-50% of these patients are rendered seizure free [34].

The most common pathologic finding in patients with partial seizures is mesial temporal sclerosis which is thought to represent a gliotic scar- often the result of a prior insult such as infection or trauma [71]. Excision of this focus can lead to elimination of the seizures or significantly improved pharmacologic control in 80% of patients. CT and MRI have low sensitivity for seizure foci detection, 17% and 34% respectively [16]. FDG PET imaging can play an important role in localization of the seizure focus in patients with partial seizure disorders.

PET is very sensitive in the early detection of the functional disturbance associated with microscopic neuronal disorganization which results in epilepsy. EEG monitoring is recommended before and during the FDG uptake phase to evaluate for seizure activity that may have occurred [113]. During the interictal phase, PET imaging with FDG will demonstrate a zone of decreased glucose utilization and decreased cerebral blood flow (CBF) at the site of a seizure focus in 60 to 70% of patients with normal MRI exams [5]. In patients with intractable temporal lobe epilepsy, interictal PET shows the hypometabolism near the seizure focus in 86% of patients (reported sensitivities 60-90% for patients with temporal lobe epilepsy and 30-60% for extra-temporal lobe epilepsy [41,113]) [34]. However, the area of reduced glucose metabolism usually extends beyond the seizure onset zone [113]. Several studies have shown that visual assessment of hypometabolism with FDG PET is less accurate than quantification with a voxel-based normalized comparison with reference templates of healthy patients and co-registration with MRI [113]. Statistical parametric mapping (SPM) is an automated objective voxel-based analysis technique in which a patient's scan is compared to a matched healthy control to aid in localization of abnormalities [55]. Quantification with SPM aids in identification of the epileptogenic lobar regions and can increase the diagnostic performance of FDG PET for seizure focus detection [55,113]. SPM was found particularly useful in identifying parasagittal cortical epileptic foci, which can be missed on visual assessment [113].

A common FDG PET finding in epilepsy is the presence of additional areas of hypometabolism in 10-43% of patients [113]. An area of hypometabolism in the ipsilateral frontal lobe can be found in 20% of patients and may represent inhibitory phenomena induced by the epileptogenic focus [113].

It has been reported that the presence of cortical hypometabolism may be associated with the duration, frequency, and severity of seizures as it is seen less often in children with new onset epilepsy (about 25% of cases) compared with 80-85% of adults with intractable seizures [72]. Hypometabolism of the ipsilateral thalamus can be seen in cases of focal epilepsy (medial temporal lobe epilepsy being particularly associated with dorsal thalamus hypometabolism) [72]. Contralateral cerebellar hypometabolism can be seen in cases of frontal (mainly) or parietal lobe seizures [72].

The distribution of the PET abnormality correlates very well with the extent of the epileptogenic zone as determined by intraoperative EEG, but correlates poorly with the extent of morphological abnormalities in the resected specimen- the area of hypometabolism is often much larger than the actual area of structural abnormality [72]. FDG PET can also predict surgical outcome, as ipsilateral PET hypometabolism appears to be associated with a good outcome (86%) [72. Among patients undergoing temporal lobectomy, a quantitative asymmetry index of greater than 15% for the lateral temporal lobe indicates the patient will likely have a good surgical outcome [6]. An odds ratio of 7 has been reported for FDG PET in predicting a seizure free outcome after epilepsy surgery [72].

The sensitivity of FDG PET in extratemporal lobe epilepsy is generally less (correct localization in 30-50% of patients) [41].

PET/MRI permits simultaneous acquisition of functional and structural images [113].

Other PET agents have also been studied for the evaluation of seizures. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the CNS and has an important role in the regulation of seizure activity [113]. Benzodiazepine receptor imaging using C-11 flumazenil will demonstrate decreased activity within the involved medial temporal cortex at the seizure focus [29,113]. However, other areas of decreased uptake can also be seen in the cortex remote from the epileptic focus and the clinical utility of the agent is limited [113]. Opiate receptor imaging will demonstrate increased tracer uptake in regions of decreased FDG accumulation corresponding to the seizure focus [29].

In patients with Sturge-Weber syndrome, FDG typically shows widespread unilateral hypometabolism ipsilateral to the facial nevus [11]. In infants less than 1 year of age, however, the interictal scan often shows a paradoxical increased cortical metabolism ipsilateral to the facial nevus [11].

Cerebrovascular Disorders

Physiology, radiopharmaceuticals, and the PET exam:

Although the brain comprises only 2% of the total body mass, it accounts for 20% of the body's total basal oxygen consumption which is used almost entirely for the oxidative metabolism of glucose (the exclusive substrate for the brains energy metabolism) [80]. The brain receives about 15% of the cardiac output [80]. Cerebral blood volume, cerebral blood flow,  the cerebral metabolic rate of oxygen, and cerebral metabolic rate of glucose all reflect various aspects of cerebral homeostasis. Derangements in cerebral perfusion produce alterations in this homeostasis that can be images with PET agents.

Cerebral blood volume: With PET imaging, the regional distribution of cerebral blood volume (CBV) is imaged following the inhalation of C-11 (T1/2= 20.3 min.) or O-15 carbon monoxide (CO). Radiolabeled CO binds with high affinity to hemoglobin within red blood cells (forming carboxyhemaglobin) permitting absolute measurements of CBV. Images of CBV show the greatest concentration of activity in the dural venous and carotid sinuses. Although blood accounts for only 5% of the volume of the gray matter structures, the gray matter has a larger CBV than the white matter. The normal whole brain CBV value is 4.2 ml/100gm.

Vasodilatation is an early response to cerebral arterial occlusion and can be used to identify areas of decreased perfusion pressure. The ratio of CBV/CBF (cerebral blood flow) increases as cerebral perfusion pressure falls.

Cerebral blood flow: In the healthy brain, cerebral blood flow is normally tightly coupled with local metabolic needs [28]. Cerebral blood flow (CBF) can be measured by using O-15 water intravenously (for scanners with high count rate capabilities), O-15 carbon dioxide inhaled (for scanners with limited count rate capabilities), or C-11 butanol. O-15 labeled carbon dioxide is converted to radiolabeled water by the action of carbonic anhydrase. The whole brain average CBF is approximately 50 ml/100 gm/min [80]. The gray matter CBF is 2.5 to 3 times greater than that of the white matter (80 versus 20 ml/100gm/min.) [80]. Electrical activity in the brain diminishes at CBF values below 20 ml/100gm/min. and cell death occurs when the CBF falls below 10 ml/100gm/min.

Cerebral metabolic rate of oxygen: The cerebral metabolic rate of oxygen (CMRO₂) is measured using O-15 oxygen. A normal mean regional CMRO₂ is approximately 3.0 ml O₂/100gm/min- with the gray matter consuming approximately 6ml/100g/min and the white matter 2 ml/100g/min [80]. A minimum value of at least 1.3-1.5 ml O₂/100gm/min. is required for tissue viability. CMRO₂ is calculated from measurements of CBF, CBV, and the oxygen extraction fraction (OEF).

The oxygen extraction fraction (OEF) represents the fraction of oxygen extracted from the blood by the brain in a single capillary transit and is approximately equal to 0.4. OEF increases as blood flow decreases. OEF is calculated by using O-15 labeled O₂ (O¹⁵O). Labeled O₂ is extracted by the brain and immediately metabolized to H₂ ¹⁵O.

OEF= CMRO₂ / CBF [arterial O2 concentration]

Cerebral metabolic rate for glucose:  The brain accounts for 25% of total body glucose consumption at rest [80]. Either F-18 fluorodeoxyglucose or C-11 deoxyglucose can be used to determine cerebral metabolic rate for glucose (CMRglu). Unfortunately, C-11 deoxyglucose is a less than optimal agent, because it is metabolized and the C-11 rapidly leaves the brain in the form of labeled CO₂. FDG crosses the blood brain barrier by a carrier mediated transport mechanism similar to those operating for glucose. The agent is phosphorylated into hexokinase, but not further metabolized and it remains inside the neural cell.

Images are performed approximately 40-60 minutes after tracer injection at which time most blood-pool activity has cleared. There is generally homogeneous regional utilization of glucose within the gray matter structures of normal resting individuals (although a decline in frontal metabolism has been reported with age). The mean global CMRglu is approximately 5 mg of glucose per 100 gm/min. (or 30 umol/min/100gm) [28]. The gray-to-white matter utilization ratio is approximately 3-to-1 with white matter CMRglu ranging from 3.6-5.2 mg glucose per 100 gm/min (other authors suggest white matter CMRglu to be 15-22 umol/100g/min [80]) and gray matter ranging from 5.8-10.3 mg glucose per 100 gm/min [28].

Cerebral Infarction

In a normal resting brain, cerebral blood flow, glucose metabolism, and the cerebral metabolic rate for O₂ are linked by a constant relationship and the OEF is relatively homogeneous across the brain.

In the early phase of CVA or reduced cerebral perfusion pressure, blood flow is maintained through autoregulated arteriolar vasodilatation leading to an increase in regional cerebral blood volume (CBV) [10,28]. When the vascular response is maximal and no further dilatation is possible, rCBF will begin to decrease, however, regional oxygen extraction fraction (rOEF) will begin to increase in an effort to maintain a stable CMRO₂ [10]. With mild to moderate decreases in CBF, neuronal function can be maintained without compromise so long as OEF increases to maintain CMRO₂ (relatively preserved CMRO₂ has been shown to be an indicator of preserved neuronal integrity in regions with severely reduced CBF [100]). In severe decreased blood flow (as CBF falls below 15-18 ml/100gm/min.), oxygen extraction rises to maximal levels. Further decreases in perfusion will then lead to the onset of ischemia and a decrease in CMRO₂. The presence of increased OEF has been shown to be a powerful and independent predictor of subsequent stroke in patients with atherosclerotic cerebral vascular disease [7].

Regions with CBF of 12-22 mL/100g/min have an unstable metabolic situation and infarction may develop if low flow persists [100]. PET studies have allowed classification of three regions within areas of disturbed vascular flow [100]. An area of oligemia with a flow of greater than 22 mL/100gm/min which is not primarily damaged by the lack of blood supply [100]. A penumbra region with a flow of 12-22 mL/100gm/min  containing tissue that is still viable, but that has uncertain chances for infarction or recovery [100]. And a region with rCBF below 11-12 ml/100gm/min. or regional CMRO₂ below 65 umol/100g/min that almost always proceed to tissue necrosis [80,100]. There is usually a surrounding penumbral region (CBF 12-22 ml/100 g/min) of still viable tissue, but with uncertain chances for infarction or recovery [80]. The condition of the tissue changes with time; the extent of the penumbra and its conversion to infarction is a dynamic process, and irreversible damages spreads from the core of ischemia to its border [100]. Focal reductions in CBF and CMRO₂ mimicking acute infarction can be seen in patients with other disorders such as cerebral hemorrhage, multiple sclerosis, or infiltrating tumor. In general, CMRglu measured with FDG tends to be lower in a site of hemorrhage compared to acute ischemic infarction, although there is considerable overlap.

Misery perfusion is defined as an increase in oxygen extraction fraction (OEF) in an ischemic brain region caused by a decrease in cerebral blood flow (up to >80% from the normal value of approximately 40% [100]), presumably due to a reduction in cerebral perfusion pressure [31]. In the early infarct (within the first 24 hours, possibly up to 2 days) there is a disproportionate decrease in rCBF compared to the decreases in regional cerebral metabolic rate for oxygen (rCMRO₂) and CMRglu. These findings are termed misery perfusion (or decoupling) because rCBF is inadequate to supply the metabolic demand for oxygen and glucose [10]. During this period there is a marked increase in the rOEF in the region of infarction reflecting compensation for the reduction in total oxygen supply [10]. Misery perfusion can be identified in 80% of patients within 12 hours of the infarct, in 40% between 12 and 24 hours, and in 15% of patients beyond 24 hours.

In most cases of acute ischemic stroke, the CMRglu is reduced in the affected tissue; however, CMRglu may be increased above normal gray matter in some sections of the infarction in up to 10% of cases probably secondary to increased anaerobic glycolysis. In general, CMRglu is reduced less than CMRO₂. During acute ischemia the CMRO₂ appears to be the most important determinant of tissue viability. During the early portion of the post-infarction period, depending on the site and severity of obstruction, ischemic cerebral tissue may be salvageable. Tissue pH is reduced under conditions of acute ischemia, but is typically alkalotic by 5 days following the infarction.

By one week post infarction there is a reversal of the previous pattern noted- with persistent vasodilatation there is increased rCBF associated with decreased or unchanged glucose utilization due to decreased demand for oxygen metabolism in infarcted brain tissue [10,28. This uncoupling of flow and metabolism in which the CBF exceeds metabolic demands represents luxury perfusion. Although this phenomenon has typically been described as occurring in the subacute phase (72 hours or more after the onset of symptoms), hyperperfusion has been found as early as within the first 24 hours- possibly related to revascularization with development of collateral flow or from endothelial injury [53]. By one month post-infarct, a matched decrease in rCBF, rCMRO₂, and glucose metabolism is seen indicating irreversibly infarcted tissue. Arteriovenous malformations (AVMs) also create a situation in which local blood flow greatly exceeds local oxygen utilization and cannot be distinguished from a subacute infarction with luxury perfusion by PET imaging.

PET imaging has also demonstrated widespread metabolic changes in structures remote form the site of infarction [10]. Crossed cerebellar diaschisis refers to a decrease in cerebellar blood flow and oxygen metabolism contralateral to the site of cerebral infarction during the first 2 months post event [10]. Interruption of the cerebro-ponto-cerebellar pathway is the proposed mechanism for this finding. Other remote function effects include decreased metabolism in the ipsilateral thalamus and caudate [10]. A decline in metabolic activity in the primary visual cortex ipsilateral to an infarct which involves the anterior visual pathways reflects a clinical homonymous hemianopsia.

Multi-infarct Dementia

MID is characterized by multifocal, asymmetric matched reductions of rCBF and rCMRglu corresponding to the locations of cortical and subcortical infarcts [8].

Arteriovenous Malformations

These lesions classically demonstrate increased regional cerebral blood volume ipsilateral to the malformation, associated with significantly decreased glucose metabolism.

Neuropsychiatric Disorders:

Dementia:

The most common cause of neurodegenerative disease in the oder population is Alzheimer disease [61]. PET imaging has been used for the assessment of dementia. When performing quantitative measurements on PET exams performed on elderly patients for dementia, it is important to remember to correct for age-related volume loss. Partial-volume averaging due to expanded sulci can result in PET measurements that underestimate true values [1]. When such corrections are made, it can be demonstrated that there is no decline in cerebral blood flow in healthy elderly individuals (except for the oribitofrontal cortex) [1,2]. A decline in dopamine activity with age, however, has been documented [2].

Mild cognitive impairment:

Symptoms and milder degrees of cognitive impairment precede the dementia of AD by several years [61]. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and a dementia disorder- especially Alzheimer's disease (AD) [54]. MCI is characterized by memory impairment or other cognitive function, but with preserved activities of daily living [54]. It is estimated that the prevalence of MCI rises from 6.7% for ages 60-64 years to 25% for ages 80-84 years [106]. About 12% of patients with the amnestic form of MCI progress to AD each year, and up to 80% by 6 years [54]. However, 30-40% of patients with MCI do not progress at all [61]. Other authors state that MCI can remain stable over 5 years in 50% of patients, but that 10-15% of MCI patients progress to dementia annually [106].

Alzheimer's Disease:

Clinical:

Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with gradual deterioration in cognition, function, and behavior [16]. Alzheimer disease is characterized by the formation of two different insoluable protein aggregates- beta amyloid plaques (which consist of aggregated beta-amyloid protein) and neurofibrillary tangles (which consist of aggregates of hyperphosphorlylated tau protein) [77]. A? deposition and NFTs can lead to disruptions in axonal growth, axonal transport, and axonal signal propogation [106].

Decreasing mortality with an ever greater elderly population has led to a rising prevalence of senile dementia [4]. AD is presently the most prevalent neurodegenerative disorder accounting for 50-80% of cases of dementia [40,54,61,93]. The prevalence of AD is below 1% in people aged 60-64y, but shows an almost exponential increase with age (doubling every 5 years after the age of 60 years) [35,61,93]. It is estimated that 8% of people over the age of 65 years suffer from Alzheimer's disease and the prevalence climbs with increasing age (about 25-30% in patients over the age of 85 years) [15,16,61]. The female to male prevalence of AD is 70%- likely related to the longer life expectancy of women [35]. Alzheimer's disease (AD) affects over 4 million people in the United States and the condition is tremendously costly to patients, their families, and society [4]. AD progresses incidiously with initial sparing of sensory and motor function [15,16]. Unfortunately, the condition frequently goes unrecognized or is not properly clinically diagnosed until it's more advanced stages [15,16].

The cause of AD is likely multifactoral [106]. Recent studies have identified certain genetic risk factors for Alzheimer's disease. Apolipoprotein (APOE), a gene on chromosome 19, has been reported to have an association with late onset AD [57,61]. The presence of APOE-4 allele increases the risk for AD, while the APOE-2 allele appears to have a protective effect. Patients with the APOE-4 allele may prove to benefit from early PET imaging in order to identify changes suggestive of AD prior to the onset of clinical symptoms. A rare familial form of AD also exists with autosomal dominant inheritance and nearly 100% penetrance [32]. Three gene mutations have been linked to early-onset familial AD- these are the genes for amyloid precursor protein, presenilin 1, and presenilin 2 [61].

CSF fluid analysis is also used for the evaluation of suspected Alzheimer disease [49]. A decrease in CSF beta-amyloid 1-42 (CSF A?₄₂) and increase tau level are felt to indirectly reflect AD [49,65]. Elevated CSF tau levels correlate with neurofibrillary pathophysiology at autopsy [65]. However, elevated CSF tau levels are not specific for AD and can be seen in other conditions such as stroke and head trauma [65].

The prodromal stage of AD is considered mild cognitive impairment (MCI) which is defined by the presence of objective cognitive impairment greater than expected for age, but without significant functional decline and preservation of activities of daily living [82,89,93]. Progression to AD has been reported in approximately 10-15% of MCI patients annually, however, not all cases of mild cognitive impairment progress to AD [89,93]. The diagnosis of AD is classified as "definite" if there has been histologic confirmation, "probable" if there is typical clinical symptoms without histologic confirmation, and "possible" if there are atypical clinical features, but no alternative diagnosis is apparent [63]. The clinical diagnosis of probable AD shows only modest sensitivity (71-81%) and specificity (approximately 70%) with the postmortem exam [87].

There is no cure for AD [61] However, accurate early diagnosis is very important as medications (cholinesterase inhibitors such as Donepezil hydrocholride, galantamine, and rivastigmine or the glutamatergic moderator memantine) are now available [61]. These agents have been shown to improve, stabilize, or delay the memory and other cognitive loss that occurs in mild to moderate disease [15,16,20,35,61]. A delay in the implementation of therapy may also have long term consequences [20]. Patients with AD in whom the start of cholinesterase inhibitor therapy is delayed demonstrate fewer benefits than do patients starting therapy early in the course of AD [35].

Pathology:

Pathologically AD is characterized by a reduction in the number of large cortical neurons in the temporal and frontal cortex (neuronal loss and atrophy) and by the appearance of senile or amyloid plaques (extracellular deposits of beta-amyloid protein) and neurofibrillary tangles (intracellular aggregates of tau proteins that interfere with the assembly and stability of the neuroskeleton) [16,38,54]. Tau protein is a phosphoprotein component of the cytoskeletal microtubule system [65,104]. It's role is stabilization of the microtubules which is critical for intracellular transport and cytoskeletal support [104]. In AD, tau becomes hyperphosphorylated, dissociates from microtubules, assumes a paired helical filament configuration, and is what forms insoluable neurofibrillary tangles inside neurons [65]. The mechanisms leading to tau hyperphosphorylation and aggregation have not been fully elucidated [104].

It should be noted that about 30% (20-40% [73] of cognitively normal elderly subjects have AD pathologic features at autopsy- typically characterized by neocortical diffuse amyloid plaques, but no extensive neurofibillary tangles (suggesting that amyloid develops first, while the neurofibillary tangles appear later [65]. Also- in patients with AD, amyloid accumulation does not parallel cognitive decline [73]. Longitudinal studies suggest that amyloid deposition tends to plateau early in the presymptomatic or prodromal phases [73]. This suggests that amyloid imaging may be a good biomarker for early detection of preclinical or early mild AD, rather than as a means of tracking AD progression [73].

Cerebral metabolic rate for glucose primarily reflects neuronal and synaptic activity, and at autopsy patients with Alzheimer's are found to have an average decrease of 50% in the density of the granular neurophil in the parietal and temporal cortices [8]. The greatest density of neuritic plaques and neurofibrillary tangles are also found in these locations [8].

PET imaging in Alzheimer's disease:

FDG PET can improve diagnostic accuracy in the evaluation of patients with cognitive decline (mild cognitive impairment or MCI) above clinical, imaging, and biomarker assessment [63,67]. Patients with mild cognitive impairment do not have dementia, but are at a 10 times higher risk for developing dementia compared to the general population [35,43]. Longitudinal studies have indicated that individuals with MCI decline to AD at a rate of 12% per year and up to 80% at 6 year followup [48]. PET FDG imaging is currently used primarily as an adjunct to the clinical determination of AD and is especially useful in differentiating AD from other dementias (including vascular dementia). [16,17]. FDG PET imaging has demonstrated promise in providing a diagnosis of AD 2 to 3 years before full dementia-related symptoms manifest [16]. This observation of a reduction in metabolism in presymptomatic patients indicates that the pathophysiologic process begins before the condition is recognized clinically [35]. By confirming the diagnosis of AD, PET imaging allows for the early institution of appropriate therapy. Also- patients with negative PET scans, can be spared the expense of unnecessary treatment as data indicates that a negative PET scan strongly favors a nonprogressive outcome [63]. However, other authors have found the NPV of FDG imaging in patients with MCI to be low (65-78%) [89].

Presently, the available literature would also support the use of PET imaging for at least 2 groups of patients- those with mild or moderate cognitive impairment who meet the standard criteria for dementia (the cause of which has not been identified by an appropriate medical workup); and those patients with mild or moderate cognitive impairment who exhibit progressive cognitive dysfunction that has not reversed after a thorough medical workup [20].

Patient preparation/Imaging: The patient should fast for at least 4 hours prior to the exam [75]. A standard dose of 5-10 mCi of FDG is used for the exam [75]. Serum glucose should be recorded with a level under 140 mg/dL being mosr desireable, although this cannot always be achieved in diabetics [75]. After injection, the patient should remain in a quiet, darkened room and should be instructed to stay awake, keep their eyes open, and not verbalize [75]. If the patient's eyes are closed, there may be occipital lobe hypometabolism (which can mimic DLB) [75].

Elevated plasma glucose levels can affect the cerebral distribution of FDG resulting in reduced FDG uptake in the precuneus (the portion of the parietal lobe posterior to the sensory-motor cortex and anterior to the occipital lobe) producing an AD-like pattern in cognitively normal individuals [83]. This pattern is reversible when glucose levels are normal [83]. Although it is usually recommended to reschedule FDG brain imaging if the glucose level is greater than 150 mg/dL, even mildly elevated glucose levels (100-110 mg/dL) can be associated with this pattern of reduced activity in the rpecuneus [83].

Certain drugs can also  affect cerebral metabolism- diazepam has been shown to reduce cerebral glucose metabolism globally by 20% [75]. It is recommended that benzodiazepine used for sedation be administered following the 30 minute FDG uptake phase [75].

Imaging is typically performed 30 minutes after tracer injection using a 3-dimensional image acquisition mode [75].

Normal patients: In healthy patients, the most intense FDG uptake occurs in the subcortical putamen, caudate nucleus, and thalamus, followed by high uptake in the cortical gray matter [75]. The white matter is relatively photopenic [75].

Findings in AD: AD classically produces a pattern of bilateral parietotemporal hypometabolism [3] (which can be asymmetric early in the course of the disease [16,20]). The posterior cingulate gyri/cortex (involved with memory related functions) and the neighboring precuneus are affected in the earliest clinical and preclincal stages of AD and hypometabolism may be limited to these regions [63,75,82,93]. The medial temporal lobes- particularly the hippocampus- are also hypometabolic in AD (hippocampal glucose metabolic reductions appear to precede those in the cortical regions in cognitively normal patients before symptoms become clinically evident) [40,63,82]. There is relative sparing of the basal ganglia, thalamus, cerebellum, visual cortex, and cortex mediating primary motor and sensory functions [20,93]. The sensorimotor cortex may appear more conspicuous when contrasted with adjacent hypometabolism [75]. Abnormalities on FDG PET imaging occur even before substantial abnormalities appear on clinical or neuropsychiatric tests [8].  The combination of reduced metabolic activity in a suspicious distribution and genetic risk factors provides a means for the detection of pre-clinical disease [18]. In advanced AD, hypometabolism will also involve the frontal lobes [40].

PET FDG imaging has been shown to have a sensitivity of 92-96%, specificity of 63-89%, and an accuracy of 82-90% for the confirmation of Alzheimer's in patients that are difficult to characterize on clinical evaluation [3,4,25]. In a meta-analysis of PET data in Alzheimer's disease, the summary sensitivity was 86% (95% CI: 76%-93%) and the summary specificity was 86% (95% CI: 72%-93%) [19]. A metaanalysis of case-control studies since the year 2000, using clinical assessment as a reference standard, found FDG PET imaging to have an overall sensitivity of 96%, a specificity of 90%, and an accuracy of 93% [63].  In a study of  138 patients with a pathologically confirmed diagnosis, PET correctly identified the presence or absence of AD in 88%, with a sensitivity of 94% (89-99%; 95% CI), and a specificity of 73% (60-87%, 95% CI) [17]. The patients in this study were generally felt to have mild cognitive impairment at the time of their initial PET exam [17]. In another prospective study of patients with mild cognitive impairment (MCI) [25], PET correctly identified patients that would progress to Alzheimer's with a sensitivity of 92% and a specificity of 89%. However, the high conversion rate from MCI to AD in this study (40%) may have contributed to the very high sensitivity [25]. This study also used an automated image analysis program (NEUROSTAT) to aid in image interpretation [25]. Programs such as NEUROSTAT provide advantages in objectivity, reproducibility, and speed of image analysis as a result of automatic anatomic standardization and statistical processing [26,40]. In a comparison to ¹⁸F-florbetapir, FDG imaging yielded a significantly higher predictive value for progression from MCI to Alzheimer, however, both imaging modalities were found to be inferior to a non-imaging model [110]. Still- the best prediction accuracy was reached by combining FDG PET, amyloid PET, and non-imaging variables (APOE, FAQ, and MMSE) which yielded a 5-year free conversion rate of 100% for the low risk group, 64% for the intermediate risk group, and 24% for the high risk group [110]. 

PET imaging can aid in physician confidence in the diagnosis of AD [63]. In one study of patients with MCI, the results of the PET scan were associated with a change in diagnosis in 29% of patients [63]. PET scan findings helped to clarify the diagnosis in 56% of cases and confirm the clinical impression in 16% of cases [63].

PET imaging can also improve the accuracy in identifying early Alzheimer's without adding to the overall costs of diagnosis and treatment [15]. In patients presenting with cognitive symptoms, a negative PET indicates a lower likelihood for a progressive dementia with a specificity of about 76% [17].

PET versus SPECT for AD: FDG PET has been shown to be superior to SPECT imaging for the evaluation of AD [81]. When compared to SPECT imaging, reductions in tracer activity are significantly more pronounced for PET imaging [14]. The magnitude of the deficits on PET also correlates with the degree of cognitive impairment [16] and the correlation between dementia severity and the number of abnormal voxels is closer for PET than for SPECT [14]. Metabolic activity in the primary sensory-motor cortex, basal ganglia, thalamus, and cerebellum are typically normal in patients with Azlheimer's disease [16]. In one study comparing FDG PET and SPECT, the sensitivity and specificity for dementia vs no dementia were 85% and 90% for PET, and 71% and 70% for SPECT [81]. Overall, for the detection of AD, PET has an increased accuracy of 15-20% compared to SPECT imaging [20].  

PET imaging has also been shown to be superior to MR voxel-based morphometry (VBM) for the identification of AD, particularly in the early stage of the disorder [39].

The pattern of biparietotemporal hypometabolism is not absolutely pathognomonic for Alzheimer's and can also be seen in patients with Parkinson's disease with dementia [20], bilateral parietal subdurals [8], dementia with Lewy bodies (but will also involve the visual cortex) [16], Creutzfeldt-Jacob disease [3], or biparietotemporal infarctions [8].

The global CMRglu has also be evaluated in patients with AD and is reduced in up to 35% of Alzheimer's patients. However, this may also be seen in patients with depression, Parkinson's, following convulsion, trauma, cerebral irradiation, ECT therapy, and with drug induced impairment of consciousness. CMRglu also decreases normally in the elderly, despite maintenance of CBF, and CMRO2. Diabetic patients with poor glycemic control have also been shown to have reduced glucose metabolism in AD regions on PET imaging (with amyloid plaque accumulation) [74].

Abnormalities within the cholinergic system have been consistently identified in patients with Alzheimer's. There is a 40 to 90% decrease in the enzyme choline acetyltransferase and consequently in acetylcholine levels within the cerebral cortex. In contrast, the dopaminergic system is not abnormal in Alzheimer's patients (as it is in patients with Parkinsons).

Imaging amyloid plaques:

Cerebral amyloid accumulation appears to start decades before the onset of dementia [82]. Amyloid plaque imaging permits demonstration of a specific biomarker for AD [65]. These new radiotracers hold promise for imaging patients with AD [16]. However, about 30% of cognitively normal elderly subjects have abnormal findings on PET amyloid imaging studies [65,114]. The prevalence of cerebral amyloid increases from 10-15% at age 65 to about 50% at age 85 [82]. Older age, APOE*E4 genotype, and a family history of AD are all associated with greater amyloid PET binding in cognitively normal individuals [65].

A meta-analysis of amyloid plaque imaging found a prevalence of 88% positive exams in AD dementia (negative exams were most commonly observed in older APOE*E4 noncarriers) [87]. However- amyloid positive exams were also seen in 51% of patients with DLB, 30% of patients with vascular demntia, and 12% of patients with FTD (and the likelihood for a positive scan increased with patient age) [87]. Positive Florbetapir imaging has been reported in up to 25% of patients with FTD [84,85]. Because of a very high positivity of amyloid imaging in patients with APOE*E4, imaging may not be justified in these patients when they display classic AD findings [87].

Quantification of Aβ PET radioligand retention can be used to detect changes in Aβ plaque burden over time in response to anti-Aβ treatment [108]. SUV ratios are commonly used as a semiquantitative measure of Aβ burden, calculated by normalizing Aβ PET radiotracer retention values from a targeted brain region of interest to a reference region that is not expected to accumulate amyloid [108]. Several factors contribute to variability in measuring change in amyloid plaque density longitudinally including partial volume effects associated with the limited spatial resolution of PET imaging, meaningful physiologic changes due to underlying disease, the tracer used, consistency of acquisition conditions (patient positioning in the field of view), and tracer quantification method (distribution volume ratio versus SUR) [86,108]. Measurements of cortical tracer retention can also be contaminated by nonspecific tracer retention in white matter - therefore, lack of stability in white matter retention could lead to spurious changes in measured cortical activity [86]. Selection of an appropriate reference region that is expected to remain free of fibrillar amyloid deposition over time is of particular concern [86]. The whole cerebellum has been used frequently for florbetapir normalization [86]. However, the low position of the cerebellum in the field of view may introduce artifacts due to image truncation, alterations in scatter, attenuation correction, and counting rate and sensitivity [86]. None-the-less, the specific reference region does not seem affect the overall ability to detect Aβ reduction [108].

Appropriate use criteria for amyloid imaging include: 1- persistent or progressive unexplained mild cognitive impariment; 2- the core clinical criteria for possible Alzheimer disease are satisified, but there is an unclear clinical presentation- either an atypical clinical course or an etiologically mixed presentation; or 3- patients with progressive dementia and atypically early age of onset [107].

¹¹C-Pittsburgh Compound-B (PIB):

¹¹C-Pittsburgh Compound-B (PIB) is one agent that primarily reflects Aβ-related cerebral amyloid (it binds with high affinity to Aβ plaques, but not to neurofibrillary tangles) [43,54]. The agent can aid in differentiating AD from FTD which is not characterized by β-amyloid plaques [56]. Evidence suggests that cerebral Aβ amyloidosis starts 10 to 15 years before the first cognitive symptoms [58]. Imaging is typically performed 40-50 minutes following tracer injection [61]. Most exams are interpreted using the cerebellar gray matter as a reference region [61]. The ratio of cerebellar to cortical binding provides a reliable measure of the brain amyloid burden [61]. The upper limit of normal is between 1.3 and 1.6 [61]. Scans interpreted by visual inspection correlate well with the SUV ratio cutoff for positive exams [61].

A drawback of PIB imaging is that an on-site cyclotron is required for ¹¹C production [44]. However, attempts are being made to label the compound with ¹⁸F [47]. Also, PIB uptake does not correlate with the severity of dementia as FDG does [56,61]. PIB uptake can also be seen in diseases with AD pathology such as Lewy body dementia and up to 30% of healthy elderly people may demonstrate positive scans in an age related manner (positive scans occur in 12% of healthy patients in their 60s, 30% in their 70s, and at least 50% of those over 80 years of age) [58,61].Positive PIB scans in asymptomatic elderly patients is strongly related to the presence of APOE-4 allele- which is carried by 27% of the general population [61]. The retention of PIB in healthy individuals is associated with a greater risk of cognitive decline and a faster rate of brain atrophy [61].

¹¹C-PIB scans are positive in 50-60% of individuals with MCI [61]. A negative ¹¹C-PIB scan in a MCI patient carries a high negative predictive value for short term progression to AD (NPV up to 100% in one study) [89]. Less than 10% of PIB negative MCI patients progress to a clinical diagnosis of AD, but 20% will progress to another type of dementia such as dementia with Lewy bodies or frontotemporal dementia [61]. The test-retest error rate for the PIB standardized uptake value ratios is approximately 5-9% [86].

¹⁸F-labeled radioligands:

Three ¹⁸F-labeled radioligands for brain imaging are available- florbetaben, florbetapir (approved for imaging), and fluremetamol [61]. A positive scan demonstrating Aβ deposition in the brain is not diagnostic of AD [92]. A major limitation of amyloid PET to support a diagnosis of AD dementia is the high prevalence of amyloid positivity in normal older individuals [68]. Estimates of age-specific positivity rates for amyloid PET are less than 5% in patients 50-60 years, 10% in patients 60-70 years, 25% in those 70-80 years, and more than 50% in persons aged 80-90 years [68]. Also- amyloid PET is frequently positive in dementia with Lewy bodies [68]. Additionally, amyloid imaging detects fibrillar amyloid found in blood vessels (cerebral amyloid angiopathy) as well as interstitial fibrillar amyloid plaques [68]. Hence, it cannot distinguish between amyloid angiopathy and AD [68]. Therefore, amyloid positivity does not establish a diagnosis of AD or differentiate it from other disorders such as dementia with Lewy bodies and cerebral amyloid angiopathy [68]. A such, amyloid PET imaging is only an indicator of underlying pathology which can be useful when a particular clinical syndrome has been identified and other explanations have been adequately considered after a proper clinical evaluation [70]. Therefore, amyloid PET is limited to a subset of cognitively impaired patients, and then only under specific circumstances with the following prerequisites- a cognitive complaint with objectively confirmed impairment; AD is a possible diagnosis, but when the diagnosis is uncertain after a comprehensive evaluation by a dementia expert; and when knowledge of the presence or absence of Aβ pathology is expected to increase certainty and alter management [70]. Evidence suggests a change in diagnosis following amyloid imaging in about 30% of patients, an increase in diagnostic confidence in about 60% of cases, and a change in patient management in about 60% of cases, specifically to a change in medication in about 40% of patients [102]. Importantly, a negative result indicates the patient is unlikely to have AD and negative results in MCI patients indicates the patient is unlikely to advance to AD dementia [92].

No drug withdrawal is presently required for amyloid plaque imaging [92]. The risk of adverse events caused by the radiotracer is less than 2% and may include HA, nausea, dizziness, flushing, musculoskeletal pain, or an injection site reaction [92]. The radiation exposure from an amyloid PET study is about 4-7 mSv [92].

Florbetapir: The agent ¹⁸F- florbetapir has rapid brain uptake and binds to beta amyloid plaques (the agent washes out of normal gray matter not containing amyloid) [59,64]. The recommended dose is 10 mCI, but doses as low as 3 mCI can be used without a significant decrease in the diagnostic quality of the exam [64]. Imaging is started 50 minutes following tracer injection [61].

A negative amyloid PET scan normally demonstrates white matter uptake and little or no binding in the gray matter (there is a clear gray-white matter contrast) [92]. Some key features include a diamond-shaped clear space along the interhemispheric fissure between the frontal lobes and a "cartoon hand" appearance to the white matter uptake in the frontal region [107]. A "double convex lens" sign represents an area of decreased activity between the cerebral hemispheres along the flax [107].

A key feature for a positive exam is loss of the gray-white matter contrast, with tracer uptake extending to the edge of the cerebral cortex [92]. The cerebellar cortex is also expected to be free of Aβ deposition except in the most advanced stages of AD (cerebellar amyloid deposition can also be seen in patients with Down syndrome [95]) [92,95]. A scan is considered positive for AD if there activity in the cortical gray matter regions relative to the cerebellum [66]. Abnormal tracer uptake tends to be symmetric [92]. Cortical regions demonstrating the most distinct accumulation in Aβ positive patients include the lateral temporal and frontal lobes, the posterior cingulate cortex/precuneus, and the parietal lobes [92]. The sensorimotor cortex and visual cortex can be relatively spared [92]. There will be loss of the diamond-shaped clear space between the frontal lobes and rather than a convex area of decreased activity between the cerebral cortices, there will be a "kissing hemispheres" sign with activity extending to the falx [107].

When interpreting the exam, the impression should state clearly weather the scan demonstrates Aβ deposition in the brain or not (positive or negative for Aβ deposition) [92]. The impression should not state "the exam is diagnostic for Alzheimer disease" [92]. Sites of Aβ deposition are often discordant with sites of hypometabolism on FDG imaging [106].

Some scans may be difficult to interpret because of image blurring related to patient motion and/or atrophy with a thinned cortical ribbon [92]. Atrophied brain may lead to false-positive results due to over-estimation of tracer uptake in the thinned gray matter due to spillover from white matter uptake [92,107].

There is only modest interobserver agreement for visual exam interpretations [84] and subjective visual assessment is equal to, if not preferred over, quantitative analysis [106]. For quantitative analysis, a cortical-to-cerebellum ratio (SUVr) can be calculated [64]. A SUVr of greater than 1.1 may be considered positive for beta-amyloid plaques [64], although other authors indicate a ratio greater than 1.3-1.6 is considered positive for amyloid deposition [78]. The degree of binding does not appear to correlate with minimental status exam score [66]. There is a high test-retest reliability with Florbetapir [64]. In a post mortum study of a small number of patients, the presence or absence of Florbetapir uptake correlated with the autopsy findings in 96% of cases [59]. The sensitivity has been reported to be 95% and the reported specificity is 95% [66].

Florbetaben: Another agent is ¹⁸F-florbetaben that binds to amyloid plaques and has been shown to distinguish patients with AD from FTLD [60]. Imaging is strated 80-90minutes follwoing tracer administration [61]. In a study using Florbetaben, cortical atrophy was found to affect quantitative analysis of PET beta-amyloid imaging resulting in apparent diminished uptake [88]. Partial volume effect correction improves quantitative analysis in patients with cortical atrophy [88].

Fluremetamol: ¹⁸F-fluremetamol is structurally identical to ¹¹C-PIB and the agent performs similarly to PIB with a sensitivity of 93% and a specificity of 96% [62]. Automated quantification using the pons as a reference region has demonstrated a sensitivity of 91% and specificity of 88% [79]. The agent frequently demonstrates striatal binding on positive scans producing a striatal bridge (on negative studies there is a striatal gap) [107].

¹⁸F-FDDNP: The agent [¹⁸F] FDDNP targets amyloid senile plaques and neurofibrillary tangles and will show increased temporal-parietal accumulation of the tracer in AD [16]. In studies, a greater degree of ¹⁸F-FDDNP tracer accumulation correlates with decreased memory performance scores and decreased glucose metabolism on FDG PET imaging [18]. Both PIB and FDDNP have been shown to be able to distinguish AD from controls, but PIB binding is usually higher and there is less overlap with controls (studies have shown that PIB uptake in AD patients is nearly twice that in controls in specific cortical areas [45]) [43].

Tau/neurofibrillary tangle imaging: 111

¹⁸F-flortaucipir: AD pathology is characterized by accumulation of tau-containing neurofibrillary tangles and amyloid plaques [105]. Accumulation starts in the transentorhinal cortex before spreading to the medial and inferior temporal lobe, the parietal-occipital regions, and the rest of the neocortex [111]. Although amyloid pathology is invariably present in AD, it is not consistently associated with the severity of the clinical features or disease duration [105]. In contrast, the severity of cognitive impairment in AD parallels the tau burden/level of neocortical NFT pathology, as well as progression [1-5,111]. Neocortical AB plaques and age related limbic neurofibrillary tangles are also common in non-demented individuals, but neocortical neurofibrillary tangles are much less prevalent [105].

The distribution of neurofibrillary tangles (NFTs) in AD is classified into four stages [111]:

B0- no NFTs
B1- Braak stages I/II- NFTs predominantly in the entorhinal cortex and closely related areas
B2- Braak stages III/IV- abundant NFTs in the hippocampus and amygdala, with some extension into the associated cortex
B3- Braak stages V/VI- NFTs widely distributed throughout the neocortex

A level of B2 tau pathology with coexisting beta-amyloid and neuritic plaques is necessary to confer a diagnosis of AD [111].

The agent ¹⁸F-flortaucipir images tau neuropathology and binds with high affinity to paired helical filament tau in neurofibrillary tangles [109]) [105].

Studies have shown rapid uptake of the agent in the brain and subsequent clearance from the white matter (unlike the white matter retention seen with amyloid imaging agents) [105]. For scan interpretation, the amount of ¹⁸F-flortaucipir uptake in the neocortical gray matter regions is evaluated [111]. A positive scan typically shows widespread neocortical activity in the posterolateral temporal, occipital, parietal and precuneus, medial prefrontal and cingulate, and lateral prefrontal regions [111]. There is a high probability for correctly identifying patients with B3 tau pathology (sensitivity 92%-100%) [111]. There is lower sensitivity for B0, B1, and B2 tau pathology and therefore, patients with meaningful tau pathology (B2) may be missed [111]. To summerize- a positive flortaucipir scan indicates the presence of widely distributed tau neuopathology (B3) in the neocortical areas [111]. A negative scan does not rule out the presence of B2 or lower tau pathology or amyloid pathology [111]. Between 15-25% of patients with elevated AB-amyloid who are clinically diagnosed as having probable AD have subthreshold levels of cortical tau tracer retention [114].

A negative scan typically demonstrates no increased neocortical activity or shows increased neocortical activity isolated to the mesial temporal, anteriolateral temporal, or frontal regions [111]. Other authors have also commented that in healthy patients, ¹⁸F-flortaucipir scans have shown tau accumulation that is mostly restricted to the medial temporal lobes. Iron accumulation and age correlate with ¹⁸F-flortaucipir in the basal ganglia of healthy controls suggesting that iron or ferritin is a possible source of off-site binding of the agent [109]. The agent also binds to neuromelanin which increases with age [109]. Additional off-target binding of the agent has also been described in the basal ganglia, chorid plexus, and substantia nigra [114].

Former football players with chronic exposure to trauma show an anterior pattern of flortaucipir retention in the prefrontal regions and the MTL, quite distinct from the posterior pattern observed in AD [114].

PET/MR in dementia imaging:

Compared to AC PET/CT, one study has suggested that AC PET/MR images demonstrate significantly lower relative tracer signal in the frontoparietal portions of the neocortex, but relatively higher signal in the subcortical and basal regions including the anterior and posterior cigulate gyri, putamen/thalamus, hypothalamus, pons, cerebellum, and inferior frontal cortices [76]. These differences can have implications for quantitative analysis when assessing for dementia patterns [76]. The discrepancies are less pronounced on NAC images, but still persist suggesting that this may be a consequence of general differences in scanner geometry, in detector technology, in scatter characteristics, or patient position in the scanner [76].

MR imaging in AD:

Typical structural changes seen in AD occur late in the disease process [93]. The hallmark finding of AD on MR is hippocampal atrophy [82]. The average hippocampal volume reduction is 20-25% in AD and 10-15% in MCI [82]. Progressive hippocampal volume loss over 12-18 months increases the sensitivity for AD [106]. Disproportionate volume loss can also be seen involving the amygdala and temporal parietal lobes with relative sparing of the primary sensorimotor cortex [93,106].

Dementia with Lewy Bodies: 

Dementia with Lewy bodies (DLB) is a primary degenerative dementia characterized by substantial loss of nigrostriatal dopaminergic terminals, together with the presence of Lewy bodies in cortical, subcortical, and brain stem structures, and and Lewy neurites [33,69]. A significant number of DLB patients also exhibit neuritic plaques composed of fibrillar amyloid precursor protein fragments (A?) amyloid) [69]. It is the second most common degenerative dementia after Alzheimer's disease- accounting for up to 15-25% of cases of dementia in older patients [33,35,37,51,75,97]. Patients present with the clinical triad of fluctuating cognitive impairment with pronounced variations in attention and alertness, recurrent detailed visual hallucinations, and spontaneous Parkinson-like symptoms (seen in 790% of patients), as well as visual spatial problems [16,35,54,78]. DLB is distinguished from Parkinson disease dementia by presentation of dementia before or within one year of the onset of parkinsonian movement symptoms [82,93]. Two core features are necessary for a diagnosis of probable DLB, while the presence of one feature is consistent with possible DLB [37]. Based upon the clinical exam, the sensitivity for the diagnosis of probable DLB ranges from 22-83% (specificity from 79-100%) [37].

Cholinesterase inhibitors are currently the treatment of choice for DLB [16, 37]. However, neuroleptic medications can induce life threatening extrapyramidal reactions and should be avoided in DLB patients [37].

FDG PET imaging can be used to aid in differentiation of AD from DLB [63]. On FDG PET imaging there are bilateral temporal-parietal deficits similar to Alzheimers (AD), but the deficit also involves the occipital lobes (visual cortex) and cerebellum (areas typically spared in AD) [16]. One study using post mortum diagnostic validation found that glucose hypometabolism in the primary visual cortex distinguished DLB from AD with 90% sensitivity and 80% specificity [51,63]. Although reduced metabolic activity is seen in the occipital lobe, it is not affected histopathologically [33]. A preservation of metabolic activity in the posterior cingulate gyrus relative to the precuneus and cuneus (cingulate island sign) has also been described as being characteristic for DLB (100% specific; sensitivity 62-82%) [51,106]. Sparing of activity in the primary visual cortex is referred to as the "occipital tunnel" sign [106]. Greater hypometabolism is correlated with more severe dementia [82].

Because of the presence of amyloid plaques, between 50-70% of patients with DLB demonstrate cortical tracer uptake on amyloid PET imaging (aymyloid plauqes are not seen in patients with Parkinson disease) [69,78]. Other authors suggest that at least 70-80% of DLB patients have cerebral amyloid plaque [82]. ¹²³I-ioflupane imaging demonstrates variable patterns of decreased dopaminergic activity [78]. This can aid in differentiating DLB from Alzheimer disease which demonstrates preserved dopaminergic activity [78].

Imaging with dopamine transporter agents (I123-isoflupane) can also help to distinguish DLB and AD if the occipital cortex is not involved [75]. An Alzheimer disease pattern of hypometabloism and a positive dopamine transporter scan with loss of dopaminergic neurons in the substantia nigra and reduced striatal dopaminergic activity indicate that DLB is the most likely diagnosis [75].

Patients with dementia with Lewy bodies have also been found to display a significantly lower myocardial ¹²³I-MIBG uptake in comparison to healthy controls and other patients with Parkinsonian symptoms [99].

Posterior cortical atrophy (PCA) can also produce occipital hypometabolism on FDG PET imaging, as well as decreased uptake in the precuneus, posterior cingulate, and temporal parietal lobes [101,106]. Patients with PCA present with a progressive decline in visuospatial and visuoperceptural deficits, with patients often having features of simultanagnosia (inability to perceive more than a single object at one time), optic ataxia, oculomotor apraxia (a defect of controlled, voluntary, and purposeful eye movement), and dysgraphia (inability to write coherently) [101].

In DLB, MR will show variable white matter hyperintensity and cortical atrophy, with sparing of the hippocampi [106].

Frontotemporal dementia (Pick's Disease):

Frontotemporal dementia (FTD) is another cortical dementia which is less common than Alzheimers disease [8,21]. Although it is the third most common type of dementia, it is estimated to account for less than 10% of all dementia cases [93, 106]. The age of onset is typically younger than for AD, generally before age 60-65 years (FTD is the most common type of dementia in patients younger than 60 years of age [93]) [82,106]. FTD is a heterogenenous group of neurodegenerative conditions that share certain clinical features caused by progressive degeneration of the frontal and anterior temporal lobes [8,21,35,82]. FTD usually presents with changes in personality, language, and behavior (social impairment and disinhibitive and impulsive behavior), with memory dysfunction not occurring until later [8,27,75]. Cognitive disturbances typical of FTD include attention deficits and impaired executive function [54]. FTD subtypes include behavioral FTD and language-predominant cognitive decline FTD, the later of which is referred to as primary progressive aphasia (PPA) [93]. PPA is further classified into semantic, agrammatic, or nonfluent, and logopenic PPA variants [93].

At autopsy, there is frontal and temporal atrophy with neuronal loss, gliosis, inflated neurons, and Pick bodies [8]. Neuropathologic findings include the presence or absence of τ-protein, ubiquitin, and the predominant τ-isoform, as detected by immunohistochemistry [54]. Most patients with FTD show brain pathology with ubiquitin positive inclusions, whereas some FTD patients show τ-positive inclusions [54]. Familial FTD is common, and genetic mutations have been demonstrated on chromosome 17 in the τ or progranulin genes [54]. There are presently no approved pharmacologic interventions for FTD and the use of anticholinesterase-type medications should be avoided [75]. Symptomatic therapies, such as cholinesterase inhibitors (donepezil) that are effective in AD, do not have proven efficacy in FTD [85,93]. In fact, donepezil may even decrease the quality of life in patients with FTD [93].

On FDG PET imaging, hypometabolism in the frontal and anterior temporal lobes is the characteristic finding [21,75,93]. Other areas that may be involved include the anterior cingulate gyrus, uncus, insula, basal ganglia, and thalamic regions [35]. The hypometabolism is frequently asymmetric and worse on the left [21]. FDG PET can discriminate FTD from AD with more than 85% sensitivity and specificity [54]. Amyloid PET is expected to be negative in FTD, but a significant minority of patients (up to 25% [84]) can have positive scans (differing depending on the subtype of FTD and this could be related to comorbid AD) [82]. For semantic PPA, FDG imaging demonstrates a pattern of asymmetric (left greater than right) anterior temporal hypometabolism with extension into the frontoparietal cortex later in the disease process [93]. Agrammatic or nonfluent PPA typically shows hypometabolism specially involving the middle and inferior aspect if the left frontal lobe and precentral gyrus [93]. With logopenic PPA, there is commonly left lateral temporal-parietal lobe and left middle parietal hypometabolism [93].

Amyloid imaging should be negative in patients with FTD [93]. False positive Florbetapir imaging has been reported in up to 25% of FTD patients [85]. This may be in part related to prominent cortical atrophy which can make distinction between white and gray matter activity difficult [85]. Also- some patients with FTD and the APOE E4 allele (homozygous) can have elevated florbetapir uptake due to extensive neuritic plaque deposition [85].

In patients with behavioral FTD, MR imaging will demonstrate symmetric or assymetric frontal and anterior temporal atrophy, which can be severe, resulting in a knife-blade-gyri appearance (although this is a late finding) [82,93]. There is relative sparing of the parietal and occipital lobes [93]. FOr patients with language-predominant cognitive decline PPA subtypes, the following patterns of atrophy have been described: Semantic PPA- left anterior temporal lobe and hippocampal atrophy; Agrammatic or nonfluent PPA- left perisylvian cortex, inferior frontal gyrus (Broca area), abd superior temporal gyrus atrophy; and logioenic PPA- left posterior sylvian or parietal atrophy [93].

Parkinson's Disease:

Parkinson's is a neurodegenerative disorder resulting from the progressive death of dopaminergic neurons in the nigrostriatal pathway (pars compacta of the substantia nigra and locus ceruleus, and presynaptic dopaminergic nerve terminals in the caudate nucleus and putamen) [8,12]. Although the cause of the disease is unknown, the disease is associated with a gradual accumulation of the misfolded synaptic protein α-synuclein in the nervous system [96]. Symptoms consist of rigidity, bradykinesia, difficulty in initiating and stopping movement, and a resting tremor [8]. A clear response to dopaminergic therapy and the presence of either olfactory loss or cardiac sympathetic denervation are supportive clinical findings [103]. The clinical symptoms of PD have been reported to be induced after 40-50% loss of the neurons in the substantia nigra pars compacta; there was also a reduction of dopamine to about 20% of normal levels in the striatum.

Parkinson's disease can be genetic and certain genes are associated with autosomal recessive Parkinson's [98]. PARK2 is the most common - accounting for 50% of familial cases and 15% of sporadic cases with onset before 45 years [98]. The PARK2 clinical phenotype is characterized by symmetrical onset, slow progression, good and sustained response to L-DOPA, and occurrence of dyskinesias in an early stage of the disease [98]. Other features include dystonic signs at onset, hypereflexia, peripheral neuopathy, and preserved olfactory function [98]. Most patients with PARK2 have neuronal loss in the substantia nigra more than in the locus coeruleus [98]. These patients have also been shown to demonstrate preserved myocardial ¹²³I-MIBG activity, as opposed to decreased uptake and higher washout rates identified in patients with idiopathic Parkinson's disease [98].

The loss of nigrostriatal dopaminergic projection neurons of the substantia nigra pars compacta is primarily responsible for the development of typical motor symptoms [103]. Motor disturbances, however, begin only after a loss of approximately 70-80% of striatal dopamine- thus, there is a long latent period which precedes the development of clinical symptoms [12]. (Other authors indicate that symptoms are induced after 40-50% loss of the neurons in the substantia nigra pars compacta  [91].) Cognitive dysfunction occurs in 25-30% of patients with Parkinson disease and this prevalence is 6 times greater than the general population [42]. Approximately 10% of patients with Parkinson's develop a dementia [8], although other authors indicate a prevalence of around 40% [54]. The key feature of dementia in Parkinson disease is executive dysfunction- i.e.: difficulty with tasks that require generation of mental sets, planning, and cognitive sequencing [42]. There is impairment in short-term recall, attention, and visuospatial functions [54]. In addition to manifesting cognitive impairment, PD patients can manifest personality and behavioral changes along with fluctuating confusion and visual hallucinosis [54].

Cognitive impairment is frequent in PD, with up to 80% of all patients developing dementia [103]. The dementia associated with Parkinson's seems to produce a uniform cerebral hypometabloism, however, biparietal hypometabolism identical to Alzheimer's can also seen in these patients (this finding is typically not found in Parkinson's patients without dementia) [8,27].

PET imaging in Parkinson:

6-[¹⁸F] fluoro-DOPA:

L-dihydroxyphenylalanine (L-DOPA) is the immediate precursor of dopamine [36]. L-DOPA is carried into the brain by the large neutral amino acid transport system, converted into dopamine by the action of L-aromatic amino acid decarboxylse, and then stored in intraneuronal vesicles [36]. The loss of dopaminergic nerve terminals in the basal ganglia can be detected by PET imaging with 6-[¹⁸F] fluoro-DOPA (an analog of L-DOPA]) to study the presynaptic component of the nigrostriatal dopamine system and dopamine metabolism [36]. The agent crosses the blood brain barrier where it is converted into 6-[¹⁸F]-fluoro-dopamine by the action of DOPA decarboxylase and stored in the presynaptic vesicles [23,38]. Unfortunately, 6-FD is also largely metabolized peripherally by DOPA decarboxylase (DDC) to 3-O-6 -[¹⁸F]-fluorodopamine which also crosses the BBB [23]. This factor, as well as other peripheral metabolites which may cross the BBB, complicate the quantification of brain uptake of 6-FD. Pre-treatment with inhibitors of DDC, such as Carbidopa, when injected before administration of the 6-FD improve brain uptake of the tracer considerably [22]. One other problem with [¹⁸F] fluoro-DOPA imaging is that the decardoxylating enzyme can be upregulated as a compensatory phenomenon, and the uptake of ¹⁸F-DOPA may be normal in patients with early disease [36,38]. Neurogenic orthostatic hypotension and severe supine hypertension can also result in higher concentrations of tracer in the putamen [50]

The cerebral radioactivity measured after the administration of 6-FD is a function of uptake of the isotope into the brain and its subsequent metabolism to dopamine. In Parkinson's disease, decreased 6-FD uptake in the striatum has been reported with the decrease in 6-FD accumulation being much more severe in the putamen than in the caudate nucleus [24,46]. Additionally, the decreased uptake is most prominent in the caudal parts of the putamen because of the topographic organization of the nigrostriatal projection [46]. Patients in the early stage of PD have at least a 30% loss of 6-FD uptake in the putamen contralateral to the side with predominant  clinical symptoms [46]. Parkinson's patients with early disease and a continued response to L-dopa therapy retain 6-FD in the striatum better than patients with long-standing disease and a fluctuating response to therapy [30]. 6-FD imaging can also be used to monitor response to therapy and disease progression [30].

¹⁸F-FDG:

On FDG, a Parkinson disease related pattern of metabolism has been described and is characterized by relatively increased metabolism in the globus pallidus and putamen, thalamus, cerebellum, pons, and sensori-motor cortex and relative decreased metabolism in the posterior temporoparitetal occipital areas and sometimes lateral frontal area (especially in PD with cognitive impairment) [96,103]. 

A separate temor-related pattern in Parkinson disease has also been described and is characterized primarily by increases in the cerebellum and primary motor cortex [96].

Other ¹⁸F agents:

F-18 labeled derivatives of m-tyrosine have also been used to study Parkinson's disease. m-Tyrosine is a substrate for the enzyme aromatic amino acid decarboxylase which is responsible for the conversion of DOPA to dopamine. Marked reduction in activity within the basal ganglia (putamen and caudate) is seen in patients with Parkinson's disease with both 6-FD and m-tyrosine.

¹⁸F-FP-CIT PET can be used for dopamine transporter (DAT) imaging [90]. Levodopa (a dopamine agonist), catechol-O-methyl-transferase-inhibitors, and monoamine oxidase type-B inhibitors do not need to be discontinued because they are no known to influence DAT imaging [90].

Other agents:

¹¹C-raclopride is a D2 receptor agonist that has been used to detect signs of nigrostriatal degeneration [54]. An increase in D2 receptor binding was observed in patients with early PD, and a reduction in binding has been observed after levodopa treatment [54]. However, PET studies of alterations in D2 dopamine receptors have been conflicting. Patients that have been studied with C-11 N-methylspiperone, while maintained on their usual dose of L-DOPA, display essentially normal levels of dopamine receptors, despite the fact that F-18 fluoro-DOPA uptake is markedly reduced.

C-11 Nomifensine has been developed to study the dopamine reuptake system located on the presynaptic nerve terminals. This agent also demonstrates decreased uptake within the basal ganglia of Parkinson's patients.

Drug-induced Parkinson (DIP):

DIP may develop in individuals treated with dopamine receptor-blocking agents, such as neuroleptics and antiemetics, dopamine depleters, and calcium channel blockers [90]. DIP symptoms usually disappear within 2 months of discontinuation of the fofending drug [90]. DAT imaging is normal in patients with DIP because the condition occurs in the absence of presynaptic dopaminergic deficits [90].

Huntington's Disease:

Huntington's disease is a slowly progressive autosomal dominant neurodegenerative disorder characterized by choreiform (involuntary) movements, personality disorders, psychiatric symptoms, and dementia [8]. Approximately 10-15% of cases are sporadic [94]. There is cytosine-adenosine-guanine trinucleotide repeats in the short arm of chromosome 4 [94]. There are both adult (more common - 90-95% of cases) and juvenile onset forms [94]. The age of onset is variable, but it occurs most frequently in the 3rd and 4th decades of life (40-50 years) [8,94].

On anatomic imaging, there is severe neuronal loss and atrophy of the caudate nuclei, and to a lesser extent the putamen and globus pallidus [8]. The caudate and putamen are deficient in the inhibitory neurotransmitter gamma aminobutyric acid (GABA) and glutamic acid decarboxylase.

FDG PET studies demonstrate decreased metabolic activity in the caudate, even when the CT is normal and years before the onset of motor symptoms [8,13]. Unfortunately, there is overlap of local caudate metabolic rates in patients at risk for Huntington's and normal control populations [13]. Other authors describe hypometabolism in the frontal and temporal lobes and more severe deficits in the basal ganglia [94]. Global CMRglu tends to be normal in Huntington's patients, in contrast to Alzheimer's patients in which it is decreased.No cerebral amyloid deposition is seen [94].

Normal Pressure Hydrocephalus:

Clinically patients present with dementia, a gait disturbance, and urinary incontinence. ("Wet, wacky, and wobbly".) CT demonstrates moderate to severe enlargement of the frontal horns, obliteration of the sulci over the convexities, and periventricular hypodensities. The CSF pressure is normal. PET studies have demonstrated decreased metabolic activity compared to normal controls, but no regional deficit has been identified.

Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome):

PSP begins in the 6th or 7th decade of life, and the duration of illness can range from 2 to 12 years [8]. PSP is characterized by parkinsonism with bradykinesia and rigidity, postural instability, and a pseudobulbar palsy syndrome with dysarthria and dysphagia, and frontal type dementia [8,30,78]. A clinical hallmark of the disorder is oculomotor dysfunction with paralysis of vertical gaze, particularly in the downward direction (supranuclear palsy of vertical gaze), although this may be absent at disease onset [8,78,82]. In contrast to Parkinson disease, PSP manifests as a symmetric rather than asymmetric-rigid syndrome [78]. PSP also initially targets the trunk and neck, rather than the limbs, causing early postural and gait instability with falls [78,93].Concomitant cognitive impairment is typically characterized by personality change, memory impairment, and depression or apathy [94]. Disease progression is usually aggressive, with death within 6-10 years of diagnosis [94].

Gross anatomic changes which can be seen on MR include: first atrophy of the midbrain tegmentum with relative sparing of the pons producing a "hummingbird" apperance to the brainstem on midline sagittal images (seen in 67% of patients with pathologically proven PSP [112]); second, atrophy of the midbrain, preservation of the tectum, and widening of the interpeduncular cistern which produces the "Mickey Mouse" sign on axial images; and putaminal T2 hypointensity which is likely caused by iron deposition [8,82,94]. Atrophy of the dentate nuclei of the cerebellum and the cerebellar hemispheres may also be seen to some degree [8,82]. Superior cerebellar peduncle atrophy is also characteristic of the disorder [82]. There is an increase in aqueductal size, as well as in the size of the quadrigeminal, ambient, and crural cisterns [8]. Atrophy and abnormal FLAIR signal intensity of the cerebellar peduncles can also be seen [94].

Classically the condition produces a pattern of global reductions in cerebral oxygen and glucose metabolism that are most prominent in the frontal cortex [3,8]. FDG PET reveals decreased glucose metabolism in the medial, dorsal, and ventrolateral frontal areas (the anterior cingulate gyrus, supplementary motor area, precentral gyrus, and pre-motor to posterior pre-frontal areas), as well as the caudate, thalamus, and upper brain stem [78,82,103]. The clinical symptoms have been linked to predominant bilateral regional hypometabolism with vertical gaze palsy associated with hypometabolism in the anterior cingulate gyrus, repeated unprovoked falls to the thalamus, gait freezing to the midbrain, and nonfluent aphasia with left medial and dorsolateral frontal lobe hypometabolism [103].

There is no cortical deposition of amyloid on amyloid PET imaging [78]. ¹²³I-ioflupane demonstrates reduced striatal dopaminergic activity with variable patterns that may be symmetric or asymmetric and may affect the putamen or caudate nucleus [78].

Corticobasal degeneration:

Corticobasal degneration is often associated with a clinical constellation of findings termed corticobasal syndrome which includes asymmetric Parkinsonism (limb rigidity or akinesia), limb distonia or myoclonus, oro-buccal or limb apraxia, gait disturbance, cortical sensory deficit, and alien hand phenomena [82,103]. The condition can be seen with other FTD-associated diseases, as well as AD [82]. The clinical diagnosis of CBD is accurate in only about 25-50% of patients [103].

There is asymmetric frontal atrophy involving the the paracentral and parasagittal structures [82]. FDG imaging shows highly asymmetric, often unilateral, hypometabolism contralateral to predominant motor symptoms, involving the frontoparietal/parietotemporal cortex, sensorimotor cortex, prefontal cortex, caudate, and thalamus [82,103].

Multiple system atrophy

Multiple system atrophy (MSA) is a primary oligodendroglial α-synucleinopathy with consecutive neuronal degeneration [103]. MSA pathology most severly affects the substantia nigra, caudate, putamen, cerebellar white matter, pontine nuclei, inferior olivary nucleus, and medullary tegmentum [103].

On FDG imaging, MSA patients show a marked hypometabolism of the posterior putamen, pons, and cerebellum, depending on the predominant side of degeneration [103].

Creutzfeldt-Jakob disease:

CJD is a rare fatal prion neurodegenerative disease characterized by rapidly progressive dementia with myoclonus [94]. The characteristic EEG finding is periodic complexes [94]. The most common imaging finding on MR is rapidly progressive atrophy that typically involves the frontal, temporal, and parietal lobes [94]. There is T2 signal and diffusion restriction in the pulvinar of the thalami and symmetric increased signal intensity in the pulvinar and dorsomedial thalamus that produces a "hockey stick" configuration [94]. Other findings include patchy gyriform T2 hyperintensity in the cerebral cortex and increased T1 signal in the globus pallidum [94]. A classic appearance of CJD has not been described on FDG imaging [94]. No amyloid deposition should be identified [94].

PET imaging findings in Dementias [20]

Dementia	PET findings
Alzheimer's	Decreased activity in the bilateral temporal and parietal cortices. During early stages, the defects often appear asymmetric.  There is relative sparing of the basal ganglia, thalamus, cerebellum, and cortex mediating primary motor and sensory functions.
Vascular	Scattered defects in the cortical, subcortical, and cerebellar areas
Frontotemporal (Pick's)	Frontal cortex and anterior temporal and mesiotemporal decreased activity with sparing of the sensorimotor and visual cortices
Huntington's	Decreased activity in the caudate and lentiform nuclei (early) with gradual development of diffuse cortical involvement
Parkinson's with dementia	Deficits are similar to those of AD, but with more sparing of the mesiotemporal area and less sparing of the visual cortex
Dementia with Lewy bodies	Deficits are similar to AD, but with less sparing of the occipital cortex and possibly cerebellum

Psychiatric disorders:

Schizophrenia

Schizophrenia represents a heterogeneous disorder characterized by phychosis with hallucinations and delusions [9,52]. Studies have suggested an association with activated microglial cells and inflammaiton in the brain- microglial cells are the predominant population of macrophages in the brain and they are responsive to injury or infection in brain tissue [52].

The most frequently reported finding in patients with schizophrenia is decreased metabolic activity and decreased CBF in the frontal cortex- referred to as hypofrontality [9]. This finding is predominantly seen in patients with chronic schizophrenia that have a long history of neuroleptic treatment [9]. Studies have shown that chronic neuroleptic treatment increases whole brain metabolism, but this increase is less in the frontal lobes than other areas [9]. In contrast, younger patients may not demonstrate hypofrontality [9]. Hypofrontality is also more commonly identified in paranoid (45%), than non-paranoid schizophrenics (20%).

When challenged with an activation task such as the Wisconsin Card Sorting Test, most patients with schizophrenia demonstrate a failure of frontal lobe activation which is felt to be related to decreased dopamine function [9]. Because the frontal cortex is highly interconnected, an abnormality in this location may produce disturbances of activity in other cortical and subcortical structures. Unfortunately, frontal metabolic defects are not specific for schizophrenia and have also been identified in patients with affective disorders, chronic cocaine abuse, Parkinson's disease, supranuclear palsy, and advanced age [9].

Several tracers have also been used to measure dopamine receptors in schizophrenic patients and patients with Parkinson's disease: 18-F or 11-C N-methylspiroperidol (NMS), 11-C raclopride, F-18 spiperone, and Bromine-76 bromospirone. N-methylspiroperidol (NMS) is a potent antipsychotic drug that is pharmacologically similar to haloperidol. It binds to both dopamine D2 and serotonin S2 receptors (however, its binding affinity for Serotonin receptors is much lower than for the D2 receptors). D2 receptors exist on axons passing from the substantia nigra to the basal ganglia, while D1 receptors are found on axons passing from the cerebral cortex to these structures.

Following administration of NMS there is preferential accumulation of the tracer in the caudate nucleus and putamen which contain the highest densities of dopamine receptors (the corpus striatum is the site of greatest concentration of dopamine receptors in normal patients). Thalamic and cerebellar activity is low. C-11 raclopride is more sensitive to changes in dopamine concentration as it binds D2 receptors more selectively and has negligible binding to serotonin receptors. The agent can be used to monitor relative changes in synaptic dopamine concentration.

An increased number of D2 receptors in the caudate and putamen can be found in patients with untreated schizophrenia, however, patients with decreased dopamine D2 receptor concentrations have also been described. Because neuroleptics bind to dopamine receptors, the amount of available dopamine receptors demonstrated on PET imaging will reflect the amount of bound ligand (ie: NMS activity will decrease as greater amounts of the neuroleptic agent is bound). Patients receiving adequate treatment with neuroleptic drugs have approximately 90% of their dopamine receptors occupied (implying a near total blockage of dopaminergic neurotransmission). It was hoped that PET imaging could be used to identify patients that might not respond to neuroleptic therapy. Unfortunately studies have not been able to demonstrate a difference in receptor blockade between responders and non-responders [9].

The lack of consistent PET findings in patients with schizophrenia would suggest that schizophrenia is a heterogeneous disorder with subgroups of patients with different cerebral abnormalities.

Substance Abuse:

Cocaine:

11-C labeled cocaine shows a heterogeneous distribution within the brain, with maximal uptake in the basal ganglia. Studies have also demonstrated that cocaine produces decreased metabolism in the cortical and subcortical structures [9], as well as widespread abnormalities in cerebral blood flow [9]. These flow abnormalities are probably the result of cocaine induced vasoconstriction, which can lead to tissue ischemia and infarction if severe [9]. The perfusion abnormalities are mostly localized to the frontal cortex, and cerebellar flow is generally unimpaired.

Alcohol:

The region most commonly reported to be abnormal in metabolic studies of alcoholics is the frontal cortex [9]. Other studies during alcohol intoxication have demonstrated more heterogeneous decreases in metabolism, with the areas greatest affected being the occipital cortex, the cerebellum, and the prefrontal cortex- these areas also contain the highest concentration of benzodiazepine receptors in the brain [9]. Other areas which have relatively low concentrations of these receptors, such as the basal ganglia and corpus callosum, demonstrate only minimal metabolic changes following alcohol consumption.

C-11 Carfentanyl:

C-11 Carfentanyl has a high affinity for mu opiate receptors which mediate analgesia and respiratory depression. The highest concentration of opiate receptors exist in the thalamus (highest concentration of mu receptors), striatum (caudate nucleus), and amygdala. There are very low concentrations of opiate receptors in the motor-sensory and occipital cortex. The distribution of the tracer can be changed by the prior administration of naloxone (an opiate antagonist) which results in markedly decreased uptake of the agent. C-11 carfentanyl studies of patients with partial complex seizures have demonstrated increased opiate receptor binding in the temporal lobe containing the epileptic focus (corresponding to the area of decreased glucose utilization identified on FDG imaging).

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