Neuroimaging in Neuro-Therapeutics

Jose C. Masdeu, M.D., Ph.D., Pamplona, Spain
E-mail: masdeu@unav.es

Neuroimaging facilitates the diagnosis and treatment of several nervous system disorders, including:

• Stroke
• Epilepsy
• Dementia
• Tumors
• Multiple Sclerosis
• Infections
• Movement and Gait Disorders
• Anxiety

This overview highlights recent or more critical developments in the application of imaging to the treatment of each of these disorders.

Stroke

Computed tomography (CT) is still the modality of choice in most places for the imaging of acute stroke. CT defines the presence of hemorrhage and allows for the use ofthrombolysis when

• there is no hemorrhage

• if present, the area of hipodensity is no larger than one/third of the middle cerebral artery territory

• less than three hours have elapsed since onset

• and other conditions are met

In many instances, the lack of time, or of additional imaging techniques will not allow for a more precise course of action. Ideally, thrombolysis should be avoided when

1. the damage is so small that no benefit will result

2. the vascular endothelium has been damaged in a relatively large area, predisposing the patient to a hemorrhage if thrombolysis is used. As a tissue resistant to hypoxia, the endothelium is only damaged by profound ischemia.

There are imaging techniques that facilitate the identification of these two conditions:

• Perfusion CT, measuring perfusion time can provide an estimate of the viability of the various ischemic brain regions.

• Brain single photon computed tomography (SPECT) depicts the area and degree of ischemia. Normal studies, or studies showing large areas of severe ischemia would contraindicate thrombolysis.

• Even more accurate data on brain perfusion can be gained with H₂¹⁵O positron emission tomography (PET), but this technique is less widely available.

• Perfusion magnetic resonance imaging (MRI) depicts the area of decreased flow, whereas diffusion MRI depicts areas of ischemia. Areas of decreased perfusion not still ischemic (perfusion-diffusion mismatch) are good targets for thrombolysis.

• MR angiography allows for determination of arterial recanalization with thrombolysis.

The identification of the cause of ischemia or hemorrhage in a stroke is an important step to treatment. For instance, an aneurysm should be obliterated by endovascular means or clipped. A patient with cardiac embologenic disease may need cardiac surgery or chronic anticoagulation. To visualize the blood vessels and the heart four techniques are mostly used:

• MRI angiography

• Ultrasound (Doppler and echo)

• Perfusion CT

• Traditional angiography

A goal for the rapid treatment of stroke is to be able to image the brain and the heart in 30 minutes. A goal not still attainable, but the subject of current research and technological developments.

Stroke Prevention

Neuroimaging is critical for several therapeutic procedures leading to stroke prevention. Such are:

• Angioplasty and stenting of stenotic extracranial or endocranial arteries

• Obliteration of 

  • berry aneurysms

  • arteriovenous malformations

• Stenting of arteries with traumatic aneurysms

Epilepsy

In addition to the diagnosis of epileptogenic lesions, such as brain tumors, neuroimaging is now used for the identification of abnormal epileptogenic brain tissue, which can be surgically removed, often with excellent results.

MRI is the first-line study. This technique allows for the identification of:

• Brain tumors, arteriovenous malformations and other obvious lesions
• Migration disorders and other cortical malformations, such as ectopic cortex
• Lesions of the cortex, such as medial temporal sclerosis

When MRI fails to help localize adequately the origin of the seizures, two other imaging techniques are available:

• Ictal SPECT

• Ictal (only for status) or Interictal PET

Dementia

Progressive cognitive decline is often produced by Alzheimer's disease (AD). CT or MRI can be used to rule out rare tumors or other lesions that can cause a somewhat similar clinical picture, as indicated in the 2001 Guidelines of the American Academy of Neurology.

Other differential diagnostic considerations that may be clarified with neuroimaging include:

• Vascular dementia

• Diffuse Lewy-body disease

• Fronto-temporal dementia

• Other progressive focal cortical syndromes (primary progressive apraxia)

• Cortico-basal ganglionic degeneration

• Creutzfeldt-Jakob disease

The arrival of donepezil and other anticolinesterase medications, and of memantine, makes it relevant to diagnose these conditions more accurately, as some of them respond more readily to the medications.

As even more active therapies are being developed, trying to prevent the excessive deposit of beta amyloid, or even facilitating its removal from the brain, it is becoming clearer that an early diagnosis is important, if possible at the preclinical stages.

Several techniques have been used to predict which patients with mild cognitive impairment are more likely to develop progressive cognitive decline:

• Metabolic imaging of the entorhinal cortex with PET

• Functional MRI

• Volumetric MRI

Removal of amyloid by vaccines or antibodies has been effective in transgenic mice and has been tried in a preliminary clinical trial, halted when several patients developed encephalitis, likely on an immune-mediated basis.

Visualization with PET of the deposition of amyloid in the brain of patients with Alzheimer was reported in the summer of 2002.

Tumors

In clinical gene-therapy trials for recurrent glioblastomas, transduction of the herpes simplex virus type-1 thymidine kinase (HSV-1-tk) gene with subsequent prodrug activation by ganciclovir was found to be safe, but clinical response was poor. PET has been used to depict the extent of HSV-1-tk gene expression, which seemed to predict the therapeutic response.

Neuroimaging is critical for the performance of stereotactic radiosurgery, to remove small tumors and obliterate small arteriovenous malformations.

Functional neuroimaging allows for the identification of cortical regions critical for movement and speech. Tumors near these areas can be more safely resected when such information is available to the neurosurgeon.

Multiple Sclerosis

Treatment of patients with the first episode may be justified, according to the new McDonald criteria, if dissemination in time and space can be concluded from MRI studies in a given patient.

The effectiveness of new therapies for multiple sclerosis, including interferon beta and antibody-mediated suppression of T cell subtypes, is being evaluated by serial MRI, an excellent tool to detect subclinical disease progression.

The "open ring" sign distinguishes giant multiple sclerosis plaques from tumors or infections, with which can be easily mistaken on CT or MRI.

Infections

The treatment of brain abscesses may be facilitated by the feasibility of same-day outpatient biopsy, which also saves resources.

Increased signal on FLAIR and diffusion-weighted MRI helps in the diagnosis of Creutzfeldt-Jakob disease. In this disorder, signal is increased in:

• Striatum

• Pulvinar

• Dorsomedial thalamus

Movement and Gait Disorders

Electrical modulation of the subthalamic nuclei, with implanted electrodes, improves Parkinson's disease. Electrode placement is facilitated by accurate neuroimaging procedures, using MRI or CT.

Pallidal stimulation is effective for the treatment of dystonia and stimulation of the ventrolateral nucleus of the thalamus helps patients with severe essential tremor

Gait disorders can be caused by treatable disorders, such as hydrocephalus, or subdural hematomas, amenable to diagnosis by CT or MRI.

Anxiety

The combination of genetics and functional neuroimaging is being used as a powerful tool to clarify many brain pathologies, as a means to finding more powerful therapies that could then be tailored to the individual (pharmaco-genomics).

As an example, functional MRI has illustrated greater neuronal activity in response to fearful stimuli in the amygdala of individuals with the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT function and increased fear and anxiety-related behaviors.

Additional Reading

• Phelps ME. Inaugural article: positron emission tomography provides molecular imaging of biological processes.
  Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9226-33.
• Lawler A. Drug-abuse research. White House stirs interest in brain-imaging initiative. Science. 2002 Aug 2;297(5582):748-9.
• Kirshner HS. Behavioral neurology in the emergency room: language testing, brain imaging, and acute stroke therapy.
  Ann Neurol. 2001 Nov;50(5):559-60.
• Lok C. Picture perfect.
  Nature. 2001 Jul 26;412(6845):372-4