The etiologies of a cerebral infarction are multiple: thrombotic, embolic, and hemorrhagic, among others. CT and MRI have replaced radionuclide imaging with the conventional radiopharmaceuticals for several decades. Functional images are usually abnormal before anatomic images, because the physiologic dysfunction of an organ precedes the resulting anatomic changes. Positron emitters include oxygen-15 (¹⁵O, half-life = 2 minutes), nitrogen-13 (¹³N, half-life = 10 minutes), carbon-11 (¹¹C, half-life = 20 minutes), and fluorine-18 (¹⁸F, half-life = 2 hours) and require coincidence detection with a PET scanner for imaging. These radioisotopes have the advantage of being naturally part of the molecular structure of endogenous substrates. PET studies using ¹⁵O-H₂O to evaluate perfusion, ¹⁵O-O₂ to evaluate oxygen metabolism, and ¹⁸F-FDG to evaluate glucose metabolism have contributed to the understanding of the physiopathology of cerebral infarction. Because of the short half-lives of the positron emitters, these PET radiopharmaceuticals are not practical for clinical use except for ¹⁸F-FDG. ^99mTc-HMPAO and -ECD, however, allow evaluation of cerebral perfusion using the SPECT technique. SPECT images with perfusion radiopharmaceuticals can demonstrate a defect of perfusion as early as 2 hours after the onset of symptoms and before the appearance of positive findings on CT or MRI, which can take a day or more. The CT scan becomes abnormal immediately only in case of hemorrhagic stroke. The size of the defect on early SPECT perfusion images (6 hours after the onset of symptoms) seems to have the best prognostic value for the outcome of these patients.

Within the first hours to days after a stroke, there is decreased relative perfusion compared to the glucose and oxygen metabolism, a phenomenon called “misery perfusion.” Twenty-four hours to a week after infarction, the perfusion usually improves but the symptoms and crossed cerebellar diaschisis persist. There is decoupling of metabolism and perfusion, a phenomenon called “luxury perfusion,” which may last 1 to 10 days and is thought to be due to local accumulation of radicals. The luxury perfusion has usually resolved a month after the onset of infarction. In addition, there is a “penumbral zone” surrounding the infarcted area, which is ischemic and demonstrates decreased perfusion but increased oxygen extraction fraction. If perfusion to the penumbral zone can be restored, irreversible damage will not occur.

There are regions that show decreased perfusion and metabolism that are distant to the region of infarction. For example, cortical infarcts are usually associated with decreased uptake in the contralateral cerebellar hemisphere (crossed cerebellar diaschisis) owing to deafferentation, a phenomenon that occurs when the impulses through the corticopontocerebellar fibers fail to be transmitted and stimulate the contralateral cerebellar hemisphere. Other areas that can demonstrate decreased perfusion and metabolism are the ipsilateral thalamus and caudate nucleus. Infarction of specific nucleus from the thalamus results in cortical hypometabolism, while infarction of other nuclei does not, owing to specific thalamocortical tracts.

Transient ischemic attacks (TIAs) can produce the symptoms of a stroke but resolve within 24 hours. However, 60% of patients with TIAs will develop a stroke later. CT images are usually normal after a TIA, but SPECT perfusion images can be abnormal in as many as 60% of the patients in the first 24 hours and 40% a week later. In patients with TIA and a normal baseline SPECT (^99mTc-HMPAO, ^99mTc-ECD) perfusion scan, evaluation of the cerebral vascular reserve using the acetazolamide challenge test may show the ischemic area.

Evaluation of cerebral perfusion reserve can be performed using acetazolamide (Diamox), an inhibitor of carbonic anhydrase, to vasodilate the capillaries of the brain. Acetazolamide is administered at a dose of 1 g intravenously 30 minutes before administration of the radiopharmaceutical. CO₂ can be used as well but is less practical. In normal individuals, perfusion to the brain increases by 30%. The perfusion increases to a lesser extent in regions of the brain supplied by abnormal vessels that cannot vasodilate. An absolute decrease in perfusion does not occur unless there is a steal phenomenon (e.g., arteriovenous malformation).

Arteriovenous malformations are not seen on SPECT perfusion images but can shunt blood from the normal vasculature and create a steal phenomenon that can induce ischemia. The ischemic zone can be demonstrated on SPECT (^99mTc-HMPAO, ^99mTc-ECD) perfusion images. After treatment, restoration of normal perfusion pressure in vessels previously submitted to low pressure, because of the steal phenomenon, may lead to their rupture. A challenge test with acetazolamide helps identify territories with enhanced vasoreactivity that are at risk for hyperemic disturbances. SPECT perfusion images can also help monitor the treatment with embolization (8).

Occasionally, it is necessary to sacrifice a large vessel such as a carotid artery. This may occur due to trauma, large tumor encasing the vessel, or treatment of arteriovenous malformation. To assess the adequacy of collateral flow, an intra-arterial balloon catheter is inflated in the vessel at the level of projected ligation. The patient is observed for neurologic deficits with the balloon inflated for 45 minutes, and if signs and symptoms of ischemia develop, the balloon is deflated. Some patients who do not develop symptoms during the balloon occlusion test do develop neurologic deficits after permanent sacrifice of the vessel. Therefore assessment of brain perfusion with ^99mTc-HMPAO or ^99mTc-ECD during balloon occlusion has been added to the evaluation of these patients (8,10).

Subarachnoid hemorrhage is often due to rupture of an aneurysm. A delayed complication is vasospasm of major vessels, which can lead to ischemia and stroke. SPECT (^99mTc-HMPAO, ^99mTc-ECD) perfusion images can demonstrate regions of decreased perfusion secondary to vasospasm when the CT images are still normal. SPECT perfusion images can also help to monitor therapy following treatment with balloon angioplasty (9).

The intracarotid amobarbital, or Wada, test is performed to lateralize both language and memory in patients considered for temporal lobectomy. Amobarbital sodium (Amytal) is injected into a carotid artery to sedate one hemisphere, and neurologic testing is performed. One mCi of ^99mTc-HMPAO or ^99mTc-ECD can be injected together with the amobarbital sodium to monitor the distribution of amobarbital (11,12).

In closed head injury, perfusion SPECT images demonstrate perfusion deficits in a larger percentage of patients than CT images, even at remote time from the trauma (13,14).

Seizures may be due to epilepsy or to the presence of an irritating focus such as a neoplasm or infectious process. There are two types of epilepsy: (a) generalized seizures (grand mal and petit mal), thought to be due to abnormal impulses between the neocortex and the thalamic reticular system, and (b) partial seizures, due to sudden depolarization of a focal group of neurons. The partial seizures are called complex if the patient loses awareness or simple if not. Most partial seizures arise from the temporal lobe. More than half of the patients
with partial seizures become refractory to medical therapy. If the seizure focus can be localized and resected surgically, the symptoms improve or are cured. MRI scanning is helpful to localize a structural lesion that may be responsible for the seizure or to demonstrate hippocampal sclerosis. However, often both the MRI and EEG fail to localize the seizure focus. Functional imaging using both SPECT (^99mTc-HMPAO, ^99mTc-ECD) and PET (¹⁸F-FDG) has been demonstrated helpful in predicting the postsurgical outcome of these patients. Both flow and metabolism are increased during the ictal and decreased during the interictal period. ¹⁸F-FDG PET imaging appears more sensitive in demonstrating the seizure focus in the interictal state, but ^99mTc-HMPAO SPECT imaging is more suitable for ictal administration because it is rapidly taken up by the cells (7,14,15,16,17,18,19,20,21,22,23).

After being treated for high-grade brain tumors with a combination of surgery, radiation therapy, and chemotherapy, patients often develop neurologic symptoms that may be related to edema and radiation necrosis or recurrent tumor. The changes on CT and MRI are very similar for both etiologies. In the early 1980s, Di Chiro and collaborators were the first investigators to demonstrate the potential for metabolic imaging with ¹⁸F-FDG PET in differentiating recurrent high-grade from radiation necrosis (14,24,25). ¹⁸F-FDG PET can also differentiate high-grade (uptake well above the level of the white matter) from low-grade glioma (uptake close to that of white matter), and the degree of uptake in high-grade gliomas has a prognostic value (26,27,28,29,30,31,32). In patients with AIDS and brain lesions, ¹⁸F-FDG PET can differentiate lymphoma (high ¹⁸F-FDG uptake) from toxoplasmosis (low ¹⁸F-FDG uptake) (33,34,35).

The SPECT radiopharmaceuticals that can be used to differentiate radiation necrosis from recurrent high-grade tumor and high-grade from low-grade gliomas are thallium-201 (²⁰¹Tl)-chloride and ^99mTc-sestamibi.

In degenerative dementia, structural imaging will either be normal or demonstrate nonspecific cortical atrophy. Functional imaging with PET usually demonstrates a pattern of hypoperfusion or hypometabolism that correlates with different syndromes. A first step in evaluating dementing syndromes is to separate patients on the basis of whether they have signs and symptoms of motor dysfunction (cortical dementias) or not (subcortical dementias). In cortical dementia, the cortex is usually affected and the subcortical structures are spared; the patients do not have motor dysfunction but present with apraxia, aphasia, memory loss, abnormal affect (Alzheimer’s or Pick’s disease). In subcortical dementias, the basal ganglia, thalami, and brainstem are affected; the patients do have motor dysfunction (disorder of posture and tone, tremor, gait disturbance) as well as memory loss, slowing of cognition, and depression. This includes extrapyramidal syndromes (e.g., Parkinson’s disease and syndromes, Huntington’s disease, and Wilson’s disease), white matter disease (e.g., multiple sclerosis), HIV encephalopathy, and normal-pressure hydrocephalus. A mixed category includes conditions that involve both cortical and subcortical structures, such as vascular dementias (e.g., multi-infarct dementia and Biswanger’s disease), infectious dementias (e.g., Creutzfeldt–Jakob), and hypoxic encephalopathy.

Alzheimer’s disease (AD) accounts for 75% of the dementias in the elderly. These patients present with short-term memory loss and visuospatial problems. However, clinically the diagnosis is unclear in a large proportion of these patients. In advanced disease, CT and MRI demonstrate more pronounced atrophy in the temporoparietal and anterior frontal cortex, and sometimes the atrophy is severe in the hippocampus. On both ¹⁸F-FDG PET and perfusion SPECT images, there is a characteristic pattern of decreased uptake in the posterior parietotemporal cortex, probably related to neuronic depletion in these areas. These functional changes precede the atrophy seen on structural imaging. Thirty percent of the patients present with a unilateral defect first (often the left); some present with a bilateral defect. Later in the disease, there is also decreased uptake in the frontal cortex (39,40). AD can occur in conjunction with Parkinson’s and Lewy body disease. In these cases, the imaging findings are indistinguishable from AD; histopathologically, the findings are those of AD in addition to Parkinson’s or Lewy body disease. The sensitivity and specificity of posterior perfusion defect for AD are in the range of 90% (41). Posterior perfusion defects mimicking AD can be seen in other pathologies such as normal-pressure hydrocephalus, Creutzfeldt–Jakob disease, and AIDS, among others.

Frontal metabolic and perfusion deficits are a landmark for Pick’s disease but can also be found in multiple-system atrophy, progressive supranuclear palsy, nonspecific frontal gliosis, and chronic alcoholism. Pick’s disease presents clinically with personality changes, emotional disturbances, and deterioration in behavior and judgment.

In Huntington’s disease, there is decreased flow and metabolism in the caudate nucleus. These findings are present in some patients with a positive family history; therefore functional imaging may be helpful in identifying the disease before it is expressed clinically.

PET and SPECT images of multi-infarct dementia usually show multiple cortical defects. The large defects follow a vascular distribution. Sometimes vascular dementia and AD can coexist in one patient.

Numerous studies have been published to investigate various neuropsychiatric diseases—such as affective disorders, schizophrenia, obsessive-compulsive disorder, chronic fatigue syndrome, and chronic pain syndrome—mainly with PET, using ¹⁸F-FDG and labeled brain receptors. To date, there are few clinical applications, but they may develop in the future.

Normal-pressure hydrocephalus (NPH) is associated with the triad of dementia, incontinence, and ataxia. The ventricles are enlarged and the CSF pressure is normal. On radionuclide cysternography, the classic findings are early entry of the radiopharmaceutical in the lateral ventricles, which persists on 24- and 48-hour images, and impairment of flow over the convexities. Because only 40% to 87% of these patients improve
after ventriculoperitoneal shunting and owing to the high complication rate of this therapy (up to 31%), the diagnosis of NPH using radionuclide cysternography has become debatable (42).

About 80% of cases involving CSF rhinorrhea are the result of direct head trauma, 16% are iatrogenic due to surgery, and 4% are spontaneous. The major complication of CSF leakage is meningitis, occurring in 25% to 50% of untreated cases. Meningitis can occur immediately or several years after the fistula. Therefore treatment of a CSF leak is indicated as soon as it is diagnosed. Radionuclide cysternography with pledget placement is the most sensitive and specific imaging test to detect CSF leakage, especially in symptomatic patients with small or intermittent leaks (42).

To evaluate shunt patency, ^99mTc-DTPA is a satisfactory radiopharmaceutical because images are usually not obtained later than 1 hour after administration into the reservoir of the shunt. If the shunt is patent, the radiopharmaceutical should be seen free in the peritoneal cavity within 30 minutes (42).