Neu r ology and Psychiat r y 4

Neurology and Psychiatry

An early application of PET was in neurochemical imaging of the brain for assessing the regional distributions of blood flow, glucose metabolism, neuro- transmitters, enzymes, and receptors. Despite the early and the current broad PET applications in brain research, however, the clinical applications of PET in neurology and psychiatry are limited to a few clinical conditions. In this chapter, we will first briefly review normal variants and the effect of aging and drugs on the imaging pattern on PET. We will then review in relatively greater depth the more common applications of PET in epilepsy, stroke, Alzheimer’s disease, and Parkinson’s disease. We will discuss briefly the other applications in Huntington’s disease, schizophrenia, and depression. However, one must note that PET has been employed as an imaging research tool in many other conditions, including, but not limited to, movement disorders, dementia, autism, attention deficit hyperactivity disorder, bipolar disorders, anxiety disorders, personality disorders, substance abuse, and eating disorders. The discussion of the potential diagnostic utility of PET in these neuropsychiatric disorders is beyond the scope of this book. The exact role of PET in these clinical settings remains undefined, but fur- ther experience may result in expanded role of PET in the diagnostic imaging evaluation of these and many other neuropsychiatric diseases.

NORMAL VARIANTS AND EFFECTS OF AGING AND DRUGS

Normal gray matter displays much higher (about four times) glucose metabo- lism than the white matter. More prominent gray matter metabolism and blood flow is seen in the frontal eye fields (anterior to the primary motor cortex), pos- terior cingulate cortex (anterosuperior to the occipital cortex), the Wernicke region (posterosuperior temporal lobe), the visual cortex, the posterior parietal lobes, and the basal ganglia.

Brain blood flow increases to adult values during adolescence. However, whether there is decline in cerebral perfusion with healthy aging is controver- sial. The reports of regional decline may be explained by the lack of partial volume correction for the age-related cerebral volume loss and the possibility of the effect of pre-clinical dementia on blood flow.

In neonates, glucose metabolism is highest in the cerebellar vermis, brain- stem, thalamus, and the sensorimotor cortex. By three months, the metabolic activity increases in the cerebellar cortex, basal ganglia, and the occipital, temporal, and parietal cortices. By six to eight months, there is an additional increase in the metabolism of the frontal and the dorsolateral occipital cortices.

The brain glucometabolism reaches adult values by two years and then exceeds the adult values until the age of nine years, at which point the metabolic activ- ity declines and reach the adult values again by the late 20s. The greatest age- associated metabolic changes occur in the thalamus and the anterior cingulate cortex. Cortical glucose metabolism declines with advancing age, particularly in the frontal lobes with either variable or no significant change in the other areas of the brain.

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Hyperglycemia impairs cortical FDG uptake by the competition of glu- cose with FDG for the glucose receptors. Many drugs (e.g., benzodiazepines, antiepileptics) tend to decrease regional or global cerebral blood flow and glucose metabolism, which will need to be taken into account for proper image interpretation. Some drugs such as haloperidol may have mixed effects with increase in the cortical metabolic activity in some areas (cerebellum, putamen) and decrease in cortical metabolism in the other areas (frontal, occipital).

An imaging variant related to remote functional effect of a brain lesion is diaschisis. Diaschisis is referred to as the coupled reduction in both the cortical perfusion and the metabolism in an area of brain due to a remote brain lesion.

This phenomenon usually involves the cerebellum (crossed cerebellar diaschi- sis) in relation to a contralateral supratentorial cerebral lesion. However, ipsi- lateral and contralateral subcortico-cortical (thalamocortical) diaschisis may also be observed.

EPILEPSY

Epilepsy is a relatively common and potentially devastating neurologic condi- tion. Seizures can be classified as either partial or generalized. The generalized epilepsy is associated with diffuse epileptiform discharges and no focal brain lesions. In contrast, an epileptogenic focus causes the partial seizure. The 1990 National Institutes of Health Consensus Conference on Surgery for Epilepsy estimated that 10–20% of epilepsy cases prove medically intractable and that 2,000–5,000 epilepsy patients per year can benefit from surgical resection of the seizure focus.

Accurate preoperative localization of the epileptogenic region is a crucial task, which is best accomplished by combining the findings of clinical exam- ination, electroencephalography (EEG), neuropsychological evaluation, and imaging studies. Computed tomography (CT) and magnetic resonance imag- ing (MRI) are used to detect structural lesions which may be the epileptogenic regions. Ictal or interictal single-photon emission tomography (SPECT) evalu- ation of regional cerebral blood flow (rCBF) can also localize the epileptogenic region even in the absence of discernable structural abnormalities on anatom- ic imaging studies. The characteristic appearance of an epileptogenic region is relative zonal hyperperfusion on ictal SPECT and relative zonal hypoperfusion on interictal SPECT. The sensitivity of ictal rCBF tracer SPECT may approach 90%, while that of interictal SPECT is in the range of 50%.

FDG PET has proven useful in preoperative localization of the epilepto- genic region (Fig. 1). The best results have been obtained in epilepsy of tempo- ral lobe origin corresponding to mesial temporal sclerosis, for which CT and MRI have relatively low sensitivity, but metabolic abnormalities may be evident in as many as 90% of surgical candidates. Surgical excision of this focus usual- ly results in the elimination of epilepsy or marked clinical improvement.

Extratemporal epileptogenic regions may be regional or diffuse and are more difficult to identify on PET due to limited sensitivity.

FDG PET is generally performed following an interictal injection due to

the relatively short half-life of F-18, which limits the window of opportunity

during which it can be administered ictally. Also due to the brain-uptake time

of FDG, the ictal FDG studies may show not only the seizure focus but also the

areas of seizure propagation. For interictal PET, FDG should be administered in a setting, such as a quiet room and dim lights, where environmental stimuli are minimal during the 30 min following FDG administration. Pharamacologic sedation is best withheld during the tracer uptake phase, since sedation may affect FDG distribution in the brain. The characteristic appearance of interictal FDG PET is regional hypometabolism at the location of the epileptogenic lesion. In order to avoid false lateralization from subclinical seizure, which results in spurious depression of tracer localization in the contralateral tempo- ral lobe, concurrent EEG recording would be helpful. Additionally, the normal asymmetric metabolism of the temporal lobes (up to 15%) should be consid- ered.The sensitivity of interictal FDG PET approaches that of ictal rCBF SPECT in localizing the epileptogenic region.

In addition to FDG, PET tracers that assess altered abundance or function of receptors, enzymes, and neurotransmitters in epileptogenic regions have been applied to localizing the epileptogenic region.

STROKE

CT and MRI are cornerstones of the imaging evaluation of stroke. PET with various tracers, however, allows the assessment of the pathophysiology of stroke through the evaluation of several important parameters, such as cerebral blood volume, cerebral blood flow, and cerebral oxidative and glucose metabolism.

The regional cerebral blood volume (CBV) may be imaged following the inhalation of C-11- or O-15-labeled carbon monoxide (CO) through the for- mation of carboxyhemoglobin. Cerebral blood flow (CBF) can be imaged by using intravenous O-15 water and inhaled O-15 carbon dioxide. The gray mat- ter CBF is about three times greater than that of the white matter. The cerebral oxidative metabolism (CMRO

) is measured using O-15 oxygen. CMRO

is

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Figure 1: A 25-year-old woman with medically intractable epilepsy. An interictal PET scan shows asymmetric left temporal lobe hypometabolism corresponding to the epileptogenic area.

calculated from the following relationship, where OEF represents the oxygen extraction fraction which increases as blood flow decreases:

CMRO

= CBF × OEF × arterial blood oxygen concentration

FDG is used to determine the cerebral glucometabolism. As described above, the gray matter displays much greater FDG uptake than the white matter.

Cerebral blood flow, oxidative metabolism, and glucometabolism are all normally linked in the normal brain. In stroke, however, uncoupling may occur. Both the amount and the duration of the reduction in cerebral blood flow determine if irreversible tissue damage occurs. In acute ischemic stroke, the identification of viable tissue (penumbra) is important for potential inter- vention in order to restore the blood flow. These areas correspond to “misery”

perfusion areas where there is preservation of CMRO2 in view of decreased flow by increasing OEF. In subacute ischemia, some patients may have postis- chemic reactive hyperemia (“luxury” perfusion) at the periphery of the ischemic stroke. This phenomenon may represent recanalization of the occluded artery and is associated with increased CBF and low OEF. PET imag- ing assessments of rCBF, CBV, and CMRO

and glucose metabolism have been shown to aid in the clinical management decision-making by demonstrating the salvageable tissue at risk. PET can also provide a quantitative estimate of the cerebrovascular reserve by comparing the rest and the vasodilatory (e.g., acetazolamide) stress cerebral perfusion patterns. Prognosis may also be evaluated by FDG PET with the preserved glucometabolism associated with reversal of the neurologic deficits and a good clinical outcome. Table 1 below summarizes the changes in the various homodynamic parameters in relation to the clinical condition.

ALZHEIMER’S DISEASE

Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with gradual decline in cognition and behavior. It is estimated that 8% of peo- ple over the age of 65 years suffer from AD and the prevalence climbs with increasing age. The neuropathologic (neurofibrillary tangles and neuritic plaques) spread of the disease progresses from transentorhinal to the limbic and then to the neocortical brain regions. Association cortices are more severely involved, while the primary somatosensory and motor cortices, the basal gan- glia, the thalamus, and the cerebellum are relatively spared. Accurate early diag- nosis of AD is important, since early use of medications such as cholinesterase inhibitors may improve or delay the cognitive loss that occurs in mild to mod- erate disease. Additionally, there may be a psychosocial benefit for the individ-

Table 1

Clinical Condition CBF OEF CMR02

Acute ischemia Low High Low~normal

(“Misery” perfusion)

Subacute Ischemia ~High Low Low

(“Luxury” perfusion)

Chronic infarct Low Low~normal Low

ual patient if the patient becomes aware of the diagnosis before the clinical manifestation of the disease.

FDG PET demonstrates reductions in the cerebral glucometabolism, which may occur a few years before the overt clinical manifestation of disease.

A classical pattern is bilateral parietotemporal hypometabolism, which may be asymmetric (Fig. 2). FDG PET is particularly useful in differentiating the Alzheimer-type glucose metabolic pattern from the pattern of the other demen- tias and in this sense can aid with the differential diagnosis. FDG PET also has been shown to provide important prognostic information such that a negative PET scan is indicative of unlikely progression of cognitive impairment for a mean follow-up of 3 years in patients who initially present with cognitive symp- toms of dementia. Other PET radiotracers directed toward imaging the cholin- ergic system and the neurofibrillary tangles may also prove useful in the future imaging diagnosis of AD.

PARKINSON’S DISEASE

Parkinson’s disease (PD) is a progressive neurodegenerative disorder character- ized by selective death of the dopaminergic neurons in the nigrostriatal pathway.

The symptoms include motor disturbances of rigidity, bradykinesia, resting tremor, and postural imbalance, which occur after a loss of approximately 70%

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Figure 2: A 76-year-old man with a history of progressive loss of comprehension and memory. CT of the brain demonstrated mild atrophy. PET scan demonstrates relatively symmetric marked hypometabolism of the frontal, parietal and temporal lobes with sparing of the sensory motor strips, occipital lobes, cerebellum (not shown), and deep gray matter (not shown) structures.

of the striatal dopaminergic neurons. Cognitive disorder may also be observed with a prevalence of dementia that can approach 40% of patients.

PET can image the presence and severity of dopaminergic neuronal loss and the terminal dysfunction in PD. Dopamine release during motor tasks can be evaluated by the changes in receptor availability to PET ligands. The func- tional effects of focal dopamine replacement via implantation of fetal cells into putamen can also be monitored. The loss of dopaminergic nerve terminals in the basal ganglia (putamen and caudate) can be assessed in vivo by PET imag- ing with [F-18]fluoro-DOPA (a radiolabeled analog of the dopamine precursor dihydroxyphenylalanine—FDOPA) to image the presynaptic dopamine metab- olism, which is diminished in PD. Carbidopa, which inhibits the peripheral metabolism of the tracer by the enzyme DOPA decarboxylase, improves the brain uptake of FDOPA. Other PET radiotracers have also been investigated to assess the alterations in the D2 dopamine receptors (up-regulated in early PD) and the dopamine reuptake system. FDG PET may also demonstrate reductions in the glucometabolism of the basal ganglia (advanced PD) and the primary visual cortex in the occipital lobe with a relative preservation of the metabolic activity in the medial temporal lobe in contradistinction to AD.

HUNTINGTON’S DISEASE

Huntington’s disease (HD) is a progressive autosomal dominant neurodegener- ative disorder with complete penetrance characterized by chorea, psychiatric symptoms, and dementia. There is severe neuronal loss and atrophy of the cau- date and putamen. FDG PET demonstrates hypometabolism in the caudate and putamen many years before the onset of the symptoms and before evidence for atrophic changes on CT or MRI. Other PET radiotracers such as C-11 raclopride (a specific marker of D2 dopamine receptor binding), have also been shown to be useful in detecting the presence and the severity of HD by demonstrating significant reductions in the striatal, frontal, and temporal tracer.

SCHIZOPHRENIA

Schizophrenia is a heterogeneous group of psychiatric disorders characterized by disturbances of thinking, mood, and behavior, which may be associated with altered concept of reality, inappropriate emotional responses, social withdrawal, delusions, and hallucinations. A commonly described finding in patients with chronic schizophrenia, especially those with paranoid features, is hypofrontali- ty defined as hypometabolism and diminished CBF in the frontal cortex.

PET imaging of schizophrenia has also been based on the assessment of

striatal dopamine transmission, including both the presynaptic and the post-

synaptic functions. FDOPA PET has been studied to evaluate the presynaptic

DOPA decarboxylase activity in patients with schizophrenia. It appears that in

patients with paranoid symptoms there is an increase in dopamine synthesis,

while conversely in patients with depressive symptoms (e.g., catatonia), there

is low FDOPA accumulation. The postsynaptic striatal D2 receptor density has

also been studied with PET extensively. In a recent meta-analysis, a small but

significant increase in striatal D2 receptors was reported in patients with

schizophrenia as demonstrated with various PET radiotracers, including C-11

raclopride and C-11-N-methyl-spiperone. C-11 raclopride PET imaging

of striatal D2 receptors, however, has failed to demonstrate a relationship between the degree of D2-receptor occupancy and clinical response. The presynaptic striatal D1 receptor levels also appear to be relatively unaltered in schizophrenia. Additionally, studies with I-123- β-CIT and F-18-CFT have reported no significant difference in the striatal dopamine transporter (DAT) binding between schizophrenic patients and controls. PET imaging of the alterations in the serotoninergic and the γ-aminobutyric acid (GABA)-ergic systems may also prove important for monitoring schizophrenia in the future studies.

DEPRESSION

PET has been investigated in the evaluation of patients with depressive dis- orders. Radiolabeled PET tracers have been used to assess the serotoninergic system. In particular, 5-HT1A and 5-HT2A receptors and 5-HT transporters have been studied. Although overall findings suggest that there are no major alterations in the 5H2A receptor density and binding there appears to be a generalized decrease in the cortical 5-HT1A receptor binding in depression.

Reductions in 5-HT transporter levels have also been observed in depression by postmortem studies, SPECT imaging with I-123- β-CIT, and PET imaging with various selective radiolabeled tracers. Additionally studies of the dopaminergic system in depression suggest that there is no consistent rela- tionship except a potential relationship in some clinical conditions such as psychomotor retardation.

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