Huntingtons Disease

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a. PET Glucose and oxygen metabolism can be assessed using PET and 18F-labeled fluorodeoxyglu-cose (FDG), 11C-labeled glucose, and 15O-labeled oxygen. A common approach has been to use FDG to evaluate glucose metabolism. Thought to be primarily an assessment of synaptic activity (i.e., deoxyglucose uptake is maximal in the neuropil rather than in regions dominated by cell bodies), scanning of patients using FDG has provided useful observations in a wide range of disorders. Hypometabolic regions are found interictally at epileptic foci and in specific cortical and subcortical regions in a wide range of degenerative and dementing processes and also appear to reflect the malignancy grade of cerebral neoplasms, particularly gliomas (Figs. 6-8). Oxygen metabolism and extraction measurements are of greatest utility in assessing patients with cerebrovascular disease, particularly that unique subset of patients for which extracranial-intracranial bypass or other surgical reperfusion approaches are contemplated.

Asymptomatic Symptomatic

Normal Mild Moderate

Figure 6 PET studies of cerebral glucose metabolism in a patient with Alzheimer's disease demonstrating the characteristic pattern of hypometabolism that occurs in the parietal and superior temporal cortices. As the disease progresses (from left to right), hypometabo-lism worsens in both spatial extent and magnitude, ultimately involving all neocortical structures.

Figure 6 PET studies of cerebral glucose metabolism in a patient with Alzheimer's disease demonstrating the characteristic pattern of hypometabolism that occurs in the parietal and superior temporal cortices. As the disease progresses (from left to right), hypometabo-lism worsens in both spatial extent and magnitude, ultimately involving all neocortical structures.

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Figure 7 Glucose metabolism measured with PET in Huntington's disease. Two anatomical levels (rows) of a normal subject demonstrating glucose metabolism in the caudate and putamen as compared with three patients, two with mild or moderate asymptomatic Huntington's disease and one with frank symptoms. Note that in the symptomatic patient there is profound hypometabolism of the caudate and most of the putamen, whereas in the asymptomatic, gene-positive subjects, there is progressive loss of metabolism in the caudate. Such changes can be identified 5-7 years prior to the onset of symptoms in patients who carry an expanded triplet repeat sequence of the Huntington's disease gene. With advancing disease, hypometabolism extends throughout the striatum and can also involve the frontal cortices (courtesy of Scott Grafton and John Mazziotta, UCLA School of Medicine).

b. MR Spectroscopy Concentrations of a wide variety of compounds can be estimated using MR spectroscopy. Proton spectra provide information about lactate as a measure of carbohydrate metabolism. Other chemical species as well as spectra obtained from other isotopes can provide additional clues about various chemical pathways. In addition, "tracer" techniques can be employed, e.g., using 17O2, 13C-labeled glucose, analogous to those used with PET or SPECT.

5. Ligands and Neuroreceptor Imaging a. PET Ligands have been developed for PET to image both pre and postsynaptic neuroreceptors. Since one or both sides of a synapse can be affected by neuropsychiatric disease, the ability to image the integrity of both components of synaptic structure and function is useful. There are a large number of neurotransmitter systems in the human brain but

Figure 8 Interictal hypometabolism of the temporal lobe in a patient with complex partial epilepsy referable to that structure. Note the profound asymmetry of metabolism, particularly in the medical but also in the lateral portion of the temporal lobe, in six out of the seven axial images. Such studies are typically performed in the evaluation of patients who are candidates for surgical treatment of their epilepsy. In many patients, brain mapping techniques have obviated the requirement for depth electrodes and subdural grids in the presurgical evaluation of such individuals (courtesy of Jerome Engel, Jr., et al., UCLA School of Medicine; J. Engel, P. H. Crandall, and R. Rausch (1983). The partial epilepsies. In Clinical Neurosciences (R. N. Rosenberg, Ed.), pp. 1349-1380. Churchill Livingstone, New York).

Figure 8 Interictal hypometabolism of the temporal lobe in a patient with complex partial epilepsy referable to that structure. Note the profound asymmetry of metabolism, particularly in the medical but also in the lateral portion of the temporal lobe, in six out of the seven axial images. Such studies are typically performed in the evaluation of patients who are candidates for surgical treatment of their epilepsy. In many patients, brain mapping techniques have obviated the requirement for depth electrodes and subdural grids in the presurgical evaluation of such individuals (courtesy of Jerome Engel, Jr., et al., UCLA School of Medicine; J. Engel, P. H. Crandall, and R. Rausch (1983). The partial epilepsies. In Clinical Neurosciences (R. N. Rosenberg, Ed.), pp. 1349-1380. Churchill Livingstone, New York).

PET ligands have been developed for only some of these. Fewer still have been completely validated and are in clinical use.

The most extensively studied neurochemical system is the dopaminergic network. Presynaptic imaging of dopamine synthesis and reuptake have been evaluated with fluorinated (18F) ligands. The uptake, metabolism, and flux of 18F-labeled l-DOPA in presynaptic dopaminergic terminals have been used to evaluate movement disorders, particularly Parkinson's disease (Fig. 9), and a number of neuropsychiatric syndromes.

The same is true for the evaluation of presynaptic dopaminergic reuptake sites (e.g., with the WIN compounds). On the postsynaptic side, numerous ligands have been developed with a range of affinities for the different postsynaptic dopaminergic receptors. These tracers include raclopride, spiperone, and ethylspiperone. They have provided data for the movement disorders, schizophrenia, pituitary tumors, and other disorders of the brain. In addition, the labeling of drugs of abuse, such as 11C-labeled cocaine, that bind to receptors in the dopaminergic system has

Figure 9 Evaluation of patients with Parkinson's disease using PET. Glucose metabolism in Parkinson's disease demonstrates a normal pattern in such patients (PD label) when compared to a normal control (middle column). When the dopamine-specific ligand [18F]fluoro-L-DOPA is employed, however, a striking reduction in the uptake of this tracer is identified in the posterior putamen of patients with Parkinson's disease when compared to normals (columns 1 and 2). This is because the majority of the presynaptic dopaminergic terminals in Parkinson's disease are lost from the putamen at the onset of Parkinson's disease symptoms. Nevertheless, this population of synapses represents only a minority of all the synapses in this structure. As such, glucose metabolism remains normal but the uptake of fluoro-L-DOPA is dramatically reduced since this tracer images only that subpopulation of cells that have dopamine as their neurotransmitter. In patients with Parkinson's disease plus dementia, some patients also show hypometabolism of neocortex ( + DEMENTIA) similar to patients with Alzheimer's disease (see Fig. 6).

Figure 9 Evaluation of patients with Parkinson's disease using PET. Glucose metabolism in Parkinson's disease demonstrates a normal pattern in such patients (PD label) when compared to a normal control (middle column). When the dopamine-specific ligand [18F]fluoro-L-DOPA is employed, however, a striking reduction in the uptake of this tracer is identified in the posterior putamen of patients with Parkinson's disease when compared to normals (columns 1 and 2). This is because the majority of the presynaptic dopaminergic terminals in Parkinson's disease are lost from the putamen at the onset of Parkinson's disease symptoms. Nevertheless, this population of synapses represents only a minority of all the synapses in this structure. As such, glucose metabolism remains normal but the uptake of fluoro-L-DOPA is dramatically reduced since this tracer images only that subpopulation of cells that have dopamine as their neurotransmitter. In patients with Parkinson's disease plus dementia, some patients also show hypometabolism of neocortex ( + DEMENTIA) similar to patients with Alzheimer's disease (see Fig. 6).

SPM 11 C-FMZ hippocampal sclerosis p<0.001 p<0.01

been helpful as a means of exploring the neurobiology of chemical addiction.

Cholinergic tracers are in use for the study of neurodegenerative disorders such as Alzheimer's disease and markers of the serotonin system and have been employed in the evaluation of psychiatric disorders. The central benzodiazepine system can be scanned with flumazenil labeled with carbon-11. Important findings have been made with this tracer in patients with epilepsy (Fig. 10A). Finally, opioid receptors have been studied with a host of ligands that bind with varying affinities to the many subclasses of opiate receptor. These compounds have been used in the exploration of eiplepsy, psychiatric disease, and movement disorders.

b. SPECT A number of iodinated compounds have been developed and serve as analogs of the PET tracers described previously. Used in a similar fashion, relative estimates of binding and receptor uptake can be obtained with SPECT (Fig. 10B). Although the number of compounds of this type is few compared to the inventory of PET ligands, interest in their development and use will result in an ever-increasing set of SPECT tracers.

6. Electrophysiology a. EEG Electrophysiological techniques provide the best temporal resolution for studying neuronal activity in patients with neurosurgical, neurological, and psychiatric disorders. Although more limited in spatial resolution than the tomographic techniques, EEG data provide the investigator and clinician an opportunity to learn about the timing of events and their synchronicity. Particularly important in the investigation of patients with seizures, EEG has been the mainstay of diagnostic evaluation of such patients. The limited spatial resolution of scalp EEG can be overcome by the use of more invasive techniques when patients are surgical candidates. In that setting, subdural grid electrodes, depth electrodes, and cortical surface electrodes can be used to obtain local extracellular field potential recordings and electrocortico-grams.

System-specific information can be obtained with EEG when recording is accompanied by specific sensory, motor, or cognitive stimulation, a technique known as ERP recording. The resultant ERP maps are used to identify the general location and relative timing of a cortical representation of such functions in the

Figure 10 Benzodiazepine receptor imaging in patients with focal epilepsy. (A) PET evaluation with [uC]flumazenil. In patients with focal temporal lobe epilepsy from hippocampal sclerosis producing complex partial seizures, flumazenil uptake is reduced in the medial temporal lobe. These changes are typically smaller in spatial extent than hypometabolism detected with FDG-PET. Comparison of the two studies may ultimately lead to more selective surgical resections of medial temporal lobe structures in such patients. [courtesy of John Duncan, National Hospital for Neurologic Disease, Queen Square, London. From Brain (1996), 119, 1677-1687, with permission of Oxford University Press]. (B) Similar imaging can be performed using SPECT and the iodinated compound iomazenil. Although slightly lower in spatial resolution, such studies provide information comparable to that discussed for flumazenil PET imaging in patients with focal epilepsy [courtesy of A. C. van Huffelen, University of Utrecht (van Huffelen et al. 1990). From Berkovic et al. (1993). In Surgical Treatment of the Epilepsies (J. Engel, Jr., Ed.), 2nd ed., p. 238. Raven Press, New York].

brain. This approach has been used extensively to evaluate interruptions of the visual, auditory, or somatosensory systems (e.g., in multiple sclerosis) noninvasively and to provide more detailed cortical maps intraoperatively, or with subcortical or depth electrodes, in the evaluation of patients with seizure foci. Analysis of power spectra from scalp EEG and ERP recordings have also provided information of clinical use in neurodegenerative disorders and psychiatric syndromes.

b. MEG The measurement of minute magnetic fields in the brain with MEG is analogous to the measurement of electrical fields with EEG. Requiring far more complex equipment, the MEG method may have greater spatial resolution and greater accuracy in identifying electrophysiological dipoles, both at the surface and in the depths of the brain. Clinically, the method has been used to identify seizure foci and in a research setting has been employed for the experimental investigation of a wide range of neuropsychia-tric disorders. Data with this technique are limited in number due to the fact that only a small number of MEG installations are currently operational and evaluating patients clinically.

c. Transcranial Magnetic Stimulation The creation of an intense focal magnetic field in the human cerebral cortex results in the induction of an electrical current that discharges cells lying tangentially within that volume of tissue. The discharge can result in a pseudophysiologic response. That is, if the motor cortex is stimulated, the appropriate contralateral muscle groups will contract. If the visual cortex is stimulated, a subject or patient will see a flash or phosphene in the contralateral visual field. Transient high-frequency stimulation of the cortex by magnetic stimulation will temporarily and reversibly deactivate it.

This approach has been used to create reversible lesions and has also been used as a therapeutic maneuver in the treatment of chronic depression, in a fashion analogous to electroconvulsive shock therapy delivered focally to the frontal cortex. When linked to a tomographic functional imaging technique, TMS can be used to map functional pathways directly in patients and normal subjects. There are guidelines for the safe use of this technique, which must be used with caution in epileptic patients.

7. Optical Intrinsic Signal (OIS) Imaging

The newest brain mapping technique to be used in a clinical setting is optical intrinsic signal imaging. This method provides information about cortical blood flow, blood volume, and metabolism in an integrated fashion. The approach is straightforward. White light is shone onto the exposed cortex and the amount of light of different wavelengths reflected from the cortex is measured. The reflectance and wavelength composition of light changes as a function of the neural activity of the illuminated tissue as a function of blood volume, blood flow, cell swelling, and the oxidative state of the tissue (among other variables). An invasive technique, OIS is used in the operating room to provide functional maps in which neuronal activity is varied by stimulation of peripheral nerves or, in the awake patient, by the performance of behavioral (e.g., language) tasks. The method has the best spatial and temporal resolution of all the functional imaging techniques, approaching 50 mm in the spatial domain and 50 ms in the temporal domain.

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Getting to Know Anxiety

Getting to Know Anxiety

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