PET in Clinical Neurology 28

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Positron emission tomography (PET) offers a noninvasive method to investigate in vivo brain functions. It allows us to quantify neuroreceptor binding, cerebral metabolism, and blood ﬂow. A vast array of tracers has enabled inves- tigators to study various brain functions. Table 28.1 lists some of the commonly used tracers and their speciﬁc applications. PET studies may be carried out at rest, while performing certain tasks, or after administration of chal- lenge compounds.

PET is increasingly used in clinical neurology to aid with disease diagnosis in early or equivocal cases and to monitor disease progression and treatment response. This chapter discusses the main uses of PET in clinical neurology.

PET in Clinical Neurology

Dementia

Alzheimer’s disease is the most common form of dementia. It is characterized pathologically by deposition of amyloid plaques and neurofibrillary tangles. ¹⁸F-2-Fluoro- 2-deoxyglucose (FDG)-PET has been widely used to study regional cerebral glucose metabolism in dementia. Early Alzheimer’s disease patients typically exhibit posterior cingulate and temporoparietal hypometabolism of glucose (1). With progression of disease, there may also be frontal involvement (2). The degree of hypometabolism correlates with the severity of dementia (3). The glucose hypometabolism in Alzheimer’s disease results from a combination of neuronal cell loss and decreased synaptic activity, although the latter appears to be of greater im- portance (4). In one study that included 138 patients with symptoms of dementia and postmortem histopathologic examination, visual analysis of FDG PET was able to identify Alzheimer’s disease with a sensitivity of 94% and specificity of 73% (5). Patients with mild cognitive impairment (MCI) represent a large group of subjects whose cognitive deficits are not severe enough to cause

significant functional impairment or fulfill the diagnosis of dementia. MCI is heterogeneous in aetiologies and clinical presentations. It is estimated that the rate of progression from MCI to dementia is between 6% and 25% per year (6). MCI can present with PET findings similar to that found in Alzheimer’s (7). De Santi et al. (8) attempted to find out the best discriminant of various subtypes of cognitive impairment using atrophy-corrected FDG-PET.

They found that entorhinal cortex glucose metabolism is the most accurate variable to differentiate MCI from controls, whereas temporal cortex glucose metabolism is best at separating MCI from Alzheimer’s disease.

FDG-PET has been used to detect subjects at risk for Alzheimer’s disease even before onset of symptoms.

Cognitively normal carriers of the apolipoprotein E type 4 allele, a common susceptibility gene for Alzheimer’s disease, showed similar pattern of glucose hypometabolism as Alzheimer’s disease patients (9, 10), and such abnormalities can be seen several decades before possible onset of dementia (11). After a mean follow-up of 2 years, the cortical metabolic abnormality continued to decline despite relative preservation of cognitive function (12, 13).

PET may be able to help predict which of these at-risk subjects will progress to Alzheimer’s disease. Entorhinal cortex hypometabolism on FDG-PET in cognitively normal elderly can predict the progression to mild cognitive impairment (14). Arnaiz et al. showed that combined glucose hypometabolism in the left temporoparietal area and performance on the block design, a measure of visu- ospatial function, correctly predicted future development of Alzheimer’s disease from MCI in 90% of cases (15).

FDG-PET in dementia with Lewy bodies (DLB) reveals changes similar to those seen in Alzheimer’s disease, plus additional hypometabolism in primary and associative visual cortices (16). In a PET study with postmortem conﬁrmatory diagnosis, the antemortem occipital glucose hypometabolism can help distinguish DLB from Alzheimer’s disease with 90% sensitivity and 80%

speciﬁcity (17). In addition, patients with DLB can present with parkinsonism and are more likely than Alzheimer’s 453

28

PET in Clinical Neurology

Yen F.Tai and Paola Piccini

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disease patients to have nigrostriatal dopaminergic dysfunction. Reduced putamenal uptake of [¹⁸F]-6-ﬂuoro-^L- DOPA ([¹⁸F]-DOPA) is able to differentiate DLB from Alzheimer’s disease with a sensitivity of 86% and speciﬁcity of 100% (18). FDG-PET in multiinfarct dementia shows multiple focal areas of hypometabolism, the

extent of which is greater than actual pathology seen on postmortem examination, probably caused by degeneration of axons following infarct with disconnection of remote structures (19, 20). Frontotemporal dementia is associated with hypometabolism in frontal and temporal lobes (20).

Alzheimer’s disease is also characterised by degeneration of the nucleus basalis of Meynert and its ascending cholinergic innervation (21). These cholinergic neurons express the enzyme acetylcholine esterase (AChE), which degrades acetylcholine. The uptake of ¹¹C-methyl- piperidin-4-yl propionate ([¹¹C]-PMP), an AChE analogue, is markedly reduced in the neocortex, hippocampus, and amygdala in early-onset Alzheimer’s disease, whereas the reduction is found only in temporoparietal cortex and amygdala in late-onset Alzheimer’s disease (22). There was also significant correlation between cortical AChE activity and Mini-Mental State Examination scores. This, together with known beneficial effects of AChE inhibitors in Alzheimer’s disease (23), suggests cholinergic deficiency plays an important role in the pathogenesis of Alzheimer’s

18FDG

11C-PIB

Normal Alzheimer’s disease

Figure 28.1. FDG cerebral glucose metabolism parametric maps (upper panel) of a normal individual and an Alzheimer’s disease patient. The latter displays characteristic temporoparietal hypometabolism. The lower panel shows minimal [¹¹C]-6-OH-BTA-1 ([¹¹C]-PIB) uptake in the normal individual, but marked widespread uptake in the cortex and striatum of the same Alzheimer’s disease patient, indicating deposition of amyloid plaques. (Images courtesy of Paul Edison.)

Table 28.1. Common positron emission tomography (PET) tracers used to study neurologic disorders.

Application Tracer

Cerebral blood flow [¹⁵O]-H2O Oxygen metabolism [¹⁵O]-O₂

Glucose metabolism [¹⁸F]-2-Fluoro-2-deoxyglucose ([¹⁸F]-FDG) Presynaptic dopamine transporter [¹¹C]-Methylphenidate, ¹¹C-RTI Dopamine storage [¹⁸F]-6-Fluoro-L-dopa (¹⁸F-DOPA) Dopamine D1 receptors [¹¹C]-SCH23390

Dopamine D2 receptors [¹¹C]-Raclopride Central benzodiazepine binding [¹¹C]-Flumazenil Opioid binding [¹¹C]-Diprenorphine

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disease. ¹¹C-PMP PET may help distinguish patients with Alzheimer’s disease from Parkinson’s disease dementia.

The latter group showed even greater and more widespread reduction in cortical AChE activity than Alzheimer’s disease patients matched for severity of dementia (24).

Despite the characteristic patterns seen in many of the dementia syndromes, there can be considerable overlap in their PET findings. Recent efforts in developing a specific ligand for beta-amyloid plaques, such as [¹¹C]-6-OH-BTA- 1 ([¹¹C]-PIB) (Figure 28.1), may further enhance the sensitivity of PET for early diagnosis of Alzheimer’s disease and provide a biologic marker of disease progression. A recent PET study by Klunk et al. (25) showed significant [¹¹C]-PIB uptake particularly in frontal, temporal, pari- etal, and occipital cortices and the striatum in mild Alzheimer’s disease patients. ¹¹C-PIB binding correlated inversely with glucose metabolism. However, no correlation between ¹¹C-PIB uptake and cognitive performance was observed. Further studies are needed to determine the sensitivity and specificity of this tracer in diagnosing Alzheimer’s disease and in predicting conversion of MCI to Alzheimer’s disease. PET can provide important information that will help identify at-risk individuals, such as those carrying the apolipoprotein E type 4 allele or with MCI who will eventually develop Alzheimer’s disease, because timely administration of putative neuroprotective agents may prevent or delay phenoconversion.

Movement Disorders

The majority of movement disorders are characterized by dopaminergic dysfunction in the basal ganglia neuronal circuit. The tracer [¹⁸F]-DOPA is frequently used to study presynaptic dopaminergic function. Following intra- venous administration, [¹⁸F]-DOPA is taken up by dopaminergic neurons and converted to [¹⁸F]-dopamine by aromatic amino acid decarboxylase (AADC). The inﬂux rate constant (Ki) of [¹⁸F]-DOPA reﬂects dopa uptake into the neurons, AADC activity, and dopamine storage capacity. [¹⁸F]-DOPA-PET therefore provides an in vivo indicator of the function and integrity of presynaptic dopaminergic terminals. Tracers that bind to presynaptic dopamine transporters, such as [¹¹C]- methylphenidate, and dopamine terminal vesicular monoamine transporters, such as [¹¹C]-dihydrotetra-

benazine, have also been utilised as markers of presynaptic dopaminergic function.

Differentiating various types of Parkinsonian syndromes clinically, especially in the early stages of the disease, can be difﬁcult. Conventional imaging methods such as magnetic resonance imaging (MRI) may not reveal any abnormality. PET can be employed as an adjunct to clinical diagnosis in equivocal cases.

Parkinson’s disease is characterized by loss of dopaminergic neurons in pars compacta of substantia nigra, particularly in the ventrolateral tier, with lesser involvement in the dorsomedial tier (26). The loss of their corresponding striatal projection terminals is detected by [¹⁸F]-DOPA- PET as progressive decline in [¹⁸F]-DOPA Ki in the putamen in a caudal-rostral direction. The greatest decrease is seen in the putamen contralateral to the side with most severe symptoms. The caudate nucleus also becomes affected later on (27). By contrast, the more-diffuse loss of nigrostriatal dopaminergic terminals in multiple system atrophy (MSA) and progressive supranuclear palsy is dis- played by [¹⁸F]-DOPA-PET as bilateral, symmetrical re- duction in Ki in the entire striatum. Corticobasal degeneration (CBD) shows equivalent reduction in [¹⁸F]- DOPA Ki of caudate and putamen, but the striatum opposite the most affected limbs has the greatest reduction.

18F-DOPA-PET can distinguish Parkinson’s disease from the striatonigral degeneration form of MSA in 70% of cases, and Parkinson’s disease from progressive supranuclear palsy in 90% of cases (28); it is, however, less effective in discriminating between the atypical Parkinsonian syndromes.

FDG-PET is also helpful in the differential diagnosis of various Parkinsonian disorders. FDG-PET in Parkinson’s disease reveals normal or raised glucose metabolism in striatum but decreased metabolism in temporoparietal areas (29). Progressive supranuclear palsy shows bilateral striatal and frontal hypometabolism, whereas decreases in striatal, brainstem and cerebellar metabolism are found in MSA. In CBD, there is asymmetrical hypometabolism of striatum, thalamus, frontal, and temporoparietal cortex, with the hemisphere contralateral to the most affected limb displaying the greatest reduction.

Principal-component analysis can reveal an abnormal pattern of relative hypermetabolism in lentiform nucleus and hypometabolism in premotor cortex in Parkinson’s disease (30). Table 28.2 summarizes major PET ﬁndings in Parkinsonian syndromes.

Table 28.2. Summary of major PET findings in Parkinsonian syndromes.

PET tracer Parkinson’s disease Progressive supranuclear palsy Multiple system atrophy (MSA) Corticobasal degeneration (CBD)

18F-DOPA Asymmetrical reduction Symmetrical reduction Symmetrical reduction Asymmetrical reduction (caudal putamen > rostral (caudate = putamen) (caudate = putamen) (caudate = putamen) putamen > caudate)

[¹⁸F]-FDG Normal/raised in striatum Reduced in striatum and frontal Reduced in striatum, brainstem, Asymmetrical reduction in Asymmetrically reduced in cortex bilaterally and cerebellum striatum, thalamus, and frontal

temporoparietal cortex and temporoparietal cortex

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PET has been developed as a marker of disease severity and progression in Parkinson’s disease. Striatal [¹⁸F]- DOPA Ki is shown to correlate with postmortem dopaminergic cell density in the substantia nigra (31).

Cross-sectional putamenal Kiin Parkinson’s disease also correlates with motor disability (32). Longitudinal progression study of Parkinson’s disease found a 9% to 12%

annual decline in striatal [¹⁸F]-DOPA Ki(33, 34), although it follows a negative exponential decline course in which the rate of decline is fastest earlier in the course of the disease (35). Several neuroprotective/restorative trials in- volving dopamine agonists (36), neural transplantation (37), and infusion of neurotrophic factors (38) have used

18F-DOPA-PET as a marker of response to treatment, although the outcome may sometimes be confounded by potential interactions between the PET ligands and medical interventions (39).

[¹⁸F]-DOPA-PET has also identiﬁed subclinical dopaminergic dysfunction in subjects at risk for familial

parkinsonism, such as those carrying mutations in parkin (40) and PINK1 (41) genes. Parkinson’s disease patients with parkin mutations have more extensive pre- and post- synaptic dopaminergic dysfunction than other Parkinson’s disease patients matched for age and disease severity (Figure 28.2) (42), but their presynaptic striatal dopaminergic function progressed at a slower rate than idiopathic Parkinson’s disease patients (40). This ﬁnding suggests that dopamine cell loss in these patients occurs early but progresses very slowly, allowing compensatory mechanisms to take place.

PET has also been widely used to study hyperkinetic movement disorders. Huntington’s disease is an autoso- mal dominant disorder arising from expanded CAG repeats in the IT15 gene on chromosome 4. The GABAergic medium spiny projection neurons in the striatum, which express dopamine D1 and D2 receptors, are preferentially lost in Huntington’s disease. Using [¹¹C]- SCH23390 and [¹¹C]-raclopride PET, Turjanski et al. (43)

Idiopathic PD

Patient with parkin mutation

Figure 28.2. [¹⁸F]-6-Fluoro-L-DOPA ([¹⁸F]-DOPA) integrated image of a subject with idiopathic Parkinson’s disease (left) compared with that of a subject with young-onset familial Parkinson’s disease linked to parkin mutation. The latter showed a greater reduction in striatal ¹⁸F-DOPA uptake despite having similar disease duration and severity. H&Y, Hoehn &

Yahr stage; d.d., disease duration.

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found a parallel reduction in striatal D1 and D2 receptor binding in Huntington’s disease. Striatal [¹¹C]-raclopride binding decreases by approximately 5% per year in Huntington’s disease and correlates cross-sectionally with the duration and clinical severity of the disease (44).

Huntington’s disease patients also showed striatal glucose hypometabolism, with the cortex becomes pro- gressively involved with increasing severity of disease, reﬂecting the widespread nature of Huntington’s disease pathology (45). Huntington’s disease gene carriers can be identiﬁed using genetic tests but existing methods, in- cluding CAG repeat length, do not accurately predict disease onset (46). PET studies of presymptomatic Huntington’s disease carriers have found reduced striatal D2 binding and glucose metabolism in only a proportion of them (47, 48). It is likely that those nearer the onset of disease are more likely to display PET abnormalities.

Larger trials are ongoing to ascertain the accuracy of PET in identifying such subjects, as intervention at this early stage using putative neuroprotective agents may yield most beneﬁts.

Striatal D2 receptor binding and glucose metabolism are also reduced in chorea because of other degenerative conditions [e.g., neuroacanthocytosis (49)] but are pre- served or even increased in nondegenerative chorea [e.g., systemic lupus erythematosus (49) and Sydenham’s chorea (50)].

Epilepsy

Antiepileptic drugs fail to adequately control seizures in 25% of patients who have epilepsy (51). Epilepsy surgery can play a significant role in the treatment of intractable focal epilepsy, as demonstrated in temporal lobe epilepsy where surgery results in a significant improvement in the control of the seizures and quality of life (52). Modern MRI is able to identify the source of seizure in the majority of patients with focal epilepsy. However, 20% to 30% of potential surgical candidates with focal epilepsy have normal MRI (53). These patients are also less likely to become seizure free if they do undergo epilepsy surgery (54). Subtle structural abnormalities, which may only be evident through histologic examination, are often not detected by MRI (55). The main clinical use of PET in epilepsy is to localize epileptogenic foci in potential surgical candidates with focal epilepsy and to corroborate findings from other investigational modalities such as electroencephalography (EEG).

In focal epilepsy, the glucose metabolism and cerebral blood ﬂow in the region of the epileptogenic focus are increased during the ictal period (56). Immediately after seizures, the hyperperfusion gradually returns to baseline, but the glucose hypermetabolism persists for another 24 to 48 h (57). Interictal PET shows decreased glucose metabolism and blood ﬂow in the epileptogenic focus. It is

important to perform PET with concomitant scalp EEG recording to correlate PET findings with ictal status of the patients. Interictal studies in patients with temporal lobe epilepsy using FDG-PET have found a 60% to 90% incidence of temporal lobe hypometabolism (53). However, the area with abnormal cerebral blood flow and metabolism is considerably larger than the actual structural abnormality, possibly reflecting reduced synaptic inhibition or deafferentiation of neighboring neurons in areas of epileptic propagation (53). Therefore, false localizations may occur, but this can be minimized by using quantita- tive rather than qualitative assessment of regional cerebral glucose metabolism. Nevertheless, this problem has limited the usefulness of FDG-PET as a localizing tool for epileptogenic foci.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in brain. The binding of

11C-ﬂumazenil ([¹¹C]-FMZ), a speciﬁc ligand for the benzodiazepine binding site of the GABAA–central benzodiazepine receptor complex (58), is reduced by 30% in epileptogenic foci (59). An autoradiographic and histopathologic study of sclerotic hippocampi revealed that this is the result of a combination of neuronal loss and decreased density of GABAAreceptors (60). There is also a good correlation between in vivo hippocampal [¹¹C]-FMZ binding and ex vivo [³H]-FMZ autoradiographic measurements in individual patients who have undergone surgery for hippocampal sclerosis (61). One study examined 100 patients with focal epilepsy who had undergone presurgical evaluation using FDG and [¹¹C]-FMZ PET. The latter demonstrated abnormality in 94% of patients with temporal lobe epilepsy. The [¹¹C]-FMZ abnormality coincided with MRI abnormality in 81% of the cases. The area with abnormal [¹¹C]- FMZ binding is usually smaller than that seen on FDG-PET but larger than the abnormality detected on MRI (62). Another study that examined the focus-localizing ability of [¹¹C]-FMZ and FDG-PET, using extra- and intracranial EEG recordings as reference, found the former to be more sensitive and accurate (63).

Correction for partial-volume effect caused by atrophy increased the sensitivity of [¹¹C]-FMZ-PET in detecting unilateral hippocampal sclerosis from 65% to 100% in one study (64).

[¹¹C]-FMZ PET can detect abnormalities in patients with normal MRI. In a study of patients with refractory temporal lobe epilepsy and normal MRI, 16 of 18 patients showed abnormal [¹¹C]-FMZ binding in the temporal lobe, and in 7 of these the findings were concordant with clinical and EEG data (65). Three patients subsequently underwent anterior temporal lobe resection with significant clinical improvement. The authors have also identified increased white matter [¹¹C]-FMZ binding in patients with temporal lobe epilepsy and neocortical epilepsy but normal MRI, which they attributed to possible presence of heterotopic white matter neurons or

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microdysgenesis (Figure 28.3) (65, 66). These abnormalities are often undetected by MRI and may form the patho- physiologic basis of medically refractory epilepsy in some patients (51). Bilateral or multiple PET abnormalities outside epileptic foci are also associated with worse prognosis for seizure control postoperatively as they may represent underlying pathology that is potentially epileptogenic (67, 68).

The foci-localizing ability of PET, particularly [¹¹C]- FMZ-PET, can reduce the need for preoperative invasive EEG recording in the future. Some centers have proposed using PET routinely to assess patients before having epilepsy surgery. However, PET does not provide additional information if MRI has already identiﬁed an obvious cause of epilepsy such as hippocampal sclerosis (69). Therefore, PET is likely to be most useful when MRI is equivocal or normal.

PET is less useful clinically for primary generalized seizures. During seizures, cerebral glucose metabolism in- creases globally, but the interictal pattern is usually normal (53).

Stroke and Neuronal Plasticity

PET cerebral blood ﬂow and metabolism studies have provided signiﬁcant insight into the pathophysiology of stroke and the development of thrombolysis as a therapeutic approach in ischemic stroke. Following occlusion

of the artery, PET can identify a “core” region of irre- versibly damaged tissue with profoundly depressed cerebral blood ﬂow and metabolism. This core region is surrounded by the penumbra, an area with marked hy- poperfusion but relatively normal oxygen consumption, which may yet be salvaged by reperfusion (70). Survival of the penumbra correlates with the functional recovery after ischemic stroke (71). The incidence and extent of penumbra decrease with time since onset of stroke. One study showed that in 90% of patients studied within 6 h after onset of stroke, there was still a substantial amount of cortical penumbra. Such ﬁndings were detected in about one-third of patients even at 5 to 18 h after onset (72). The heterogeneity in the survival of penumbra suggests that the therapeutic window for reperfusion strategies may be different for certain subsets of patients, and this possibility should be investigated in future thrombolysis trials.

Significant recovery of cerebral functions in adult brains after insults such as stroke can occur despite limited structural recovery (73). Evidences from several PET studies suggest that recruitment of remote areas such as corresponding cortical areas of unaffected hemisphere and functional reorganization of adjacent structures are among the mechanisms responsible for this. One [¹⁵O]- H2O activation study showed that in patients who recov- ered from hemiplegic stroke there was a bilateral activation of motor cortices when moving fingers in the affected hand, whereas movement of fingers in the normal

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Figure 28.3. Voxel-based analysis of

11C-flumazenil parametric image of a patient with temporal lobe epilepsy and normal magnetic resonance imaging (MRI), showing increased ¹¹C-flumazenil uptake in the temporal lobe white matter bilaterally compared to normal controls (65). Color scale, Z-score. (From Hammers A, Koepp MJ, Hurlemann R, et al.

Abnormalities of grey and white matter [¹¹C]flumazenil binding in temporal lobe epilepsy with normal MRI. Brain 2002;125(pt 10):2257–2271. Reprinted by permission of Oxford University Press.)

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hand resulted in activation of only contralateral motor cortex (74). In another study, patients with nonﬂuent aphasia caused by a left anterior perisylvian infarction in- cluding left pars opercularis and subsequent recovery were compared with two control groups: normal subjects and anterior aphasic patients with sparing of left pars opercularis (75). During production of propositional speech, the left pars opercularis infarct group showed increased activation of homotoptic right pars opercularis when compared with the two control groups. Further under- standing of the mechanisms underlying neuronal plasticity will help design appropriate strategies for rehabilitation and identify patients who are most likely to beneﬁt from such therapy.

Conclusion

PET in clinical neurology is most useful when comple- mented by meticulous clinical information and other investigational modalities such as MRI. Its major applications in clinical neurology are localization of seizure foci in potential candidates for epilepsy surgery, especially where other imaging ﬁndings are negative or inconclusive, and as an adjunct to clinical diagnosis in equivocal cases of dementia and Parkinsonian syndromes.

When effective neuroprotective agents become available in the future, PET will have an additional role of identifying individuals at risk for developing neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, as early treatment may prevent or delay development of the disease.

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