By Robert S. Miletich

Much of the historical development of medical imaging after the time of Wilhelm Roentgen was fueled by a quest for an image of the brain.

Even with the use of X-rays, the brain in the intracranial vault remained a secret place, as it was not readily examinable by clinical practitioners because of its encasement in the bony box called the skull. The development of computed assisted tomography, now called CT, revolutionized the practice of clinical neurology in the 1970s. CT was soon overtaken by nuclear magnetic resonance imaging, now called MRI, in major part because of the better soft tissue contrast that MRI affords. CT and MRI show the anatomic structure of the brain, which is clinically important because nervous system diseases or illnesses often affect that structure, though not always. In contrast, brain disorders always affect the functioning of the brain. We are now entering into a new era, wherein we clinically have the capability of creating images of the functioning brain. This is the focus of nuclear neurology (NN), a 21st century diagnostic field now available for clinical medicine.



NN uses the techniques of nuclear medicine in order to examine the brain. Its modalities include positron emission tomography (PET), single photon emission computed tomography (SPECT) and scintigraphy. NN is also called neuromolecular imaging, because the source of its signal is from a radioisotope tagged to a molecule which demonstrates or traces some physiologic process. NN is also cellular imaging as we are measuring physiological processes, many of which reside within the brain cells. The improved diagnostic accuracy of NN directly results from this characteristic of measuring physiology through both molecular and cellular imaging.

Diagnosis of neurologic syndromes is particularly difficult because it is a two-step process. First, any particular set of neurologic signs and symptoms can be due to pathology at multiple sites in the nervous system. This, in part, is related to neural redundancy in the mediation of function. It is also due to the fact that for a neural signal to gain expression to the outside world, it must traverse through multiple levels of the nervous system. Second, there are a large number of diseases that can cause any neurologic syndrome, hence the differential diagnosis is quite wide. Since brain disorders always affect physiologic function, by assaying the appropriate physiologic process, NN provides increased sensitivity for disease detection. Since each disease process has its own functional profile, NN provides increased specificity for distinguishing between illnesses. Increased sensitivity plus increased specificity equates to increased diagnostic accuracy. The main advantages of NN over conventional imaging are: early diagnosis in the pre-diagnostic and even pre-symptomatic phases of chronic disease; differential diagnosis; and evaluation of therapy efficacy.

There are two general classes of NN exams, separated by the type of physiologic process measured, what I call basal and specific physiology. Basal physiology refers to those processes which all cells of the body engage in. All cells require intermediary metabolism in order to generate stored energy. All cells need blood perfusion for the delivery of nutrients and for the elimination of waste products. Specific physiology refers to processes which are not ubiquitous, but rather are specific to certain types of cells. There are different arrays of NN exams for different disorders. These will now be briefly reviewed.

The remarkable prevalence of dementia and cognitive impairment in the older population is creating a public health epidemic for the aging U.S. population. Dementia is a syndrome and has a wide differential diagnosis. Dementia is also the result of chronic illness. Early diagnosis improves management outcomes. Each disorder which causes dementia has its own basal physiology pattern. Thus, basal physiology imaging with cerebral perfusion SPECT (CPS) and glucose metabolism PET (FDG-PET) can have major roles. In addition, the diagnosis of Alzheimer’s disease can be aided by PET amyloid imaging, of which there are now four FDA-approved radiopharmaceuticals. The exact diagnosis of dementia is important in that drugs which are currently used in cognitively impaired patients can have adverse effects if given to the wrong patient. For instance, neuroleptics given to dementia with Lewy bodies patients or acetylcholinesterase inhibitors given to frontotemporal lobar degeneration patients can cause clinical destabilization.

Grading of brain tumors for degree of malignancy guides therapy which is offered to patients. Grading is performed with FDG-PET and slightly less effectively with thallium-SPECT. Although MRI is highly sensitive for pathology, it has poor specificity and many times cannot distinguish between tumor recurrence or treatment effect. This is the main indication for FDG-PET in brain tumors.

Epilepsy affects 1 percent of the population. It is often unclear what the underlying disorder is in patients presenting with episodic neurologic syndromes. There can be changes in the epileptic brain even when patients are seizure-free, or interictally. This can help distinguish epilepsy from transient ischemic attack or other manifestation of cerebrovascular disease and even somatization psychiatric illness. Many epilepsies can also be cured by surgically resecting the seizure focus. CPS during a seizure (ictus) is a standard diagnostic method of epilepsy centers throughout the world.

Epidemiologic studies have shown that parkinsonism is just as prevalent as dementia and cognitive impairment in the older segment of the population. It also has just as broad of a differential diagnosis as dementia. Basal physiology imaging with CPS and FDG-PET has roles in both the early diagnosis and the differential diagnosis of parkinsonism. There is also a specific physiology imaging exam available which allows us to assay the density of dopamine transporters which are present on dopamine nerve terminals. This assay is helpful for the diagnosis of Parkinson’s disease and atypical parkinsonian syndromes.

Stroke remains the No. 4 killer of humans. What is not revealed in this statistic is the prevalence of morbidity in the population because of cerebrovascular disease. We are starting to become aware of the shocking prevalence of small vessel disease in the U.S. population. Because it is a cell-based imaging method, CPS has high sensitivity for the detection of ischemia in viable cells and in distinguishing viability from cell death. The latter is an important consideration for decisions on using invasive endovascular therapies. This exactly replicates management decisions faced in cardiology.

Following closed head injury, patients often have persistent symptoms which are poorly explained by conventional imaging. Basal physiology imaging of NN can identify dysfunction in this post-concussive syndrome and help facilitate entry into appropriate treatment regimens.

Patients presenting with neurologic syndromes usually carry comorbidities of systemic illness which often cloud the diagnostic picture as to causation. These illnesses may even be inducing a low grade toxic or metabolic encephalopathy. Polypharmacy related to these disorders may even be a major factor. Basal physiology NN with CPS or FDG-PET can be helpful in this differential diagnosis as metabolic encephalopathies have a pattern revealed in NN.

A major element of many differential diagnoses for the above disorders is psychiatric illness. Somatization related to affective disorders, anxiety disorders and even psychotic disorders can mimic various neurologic disorders. These can be distinguished by NN as there are patterns on basal physiology NN which identify these.

There has been recent disturbing press on patients with disorders of consciousness. Brain injury from trauma, hypoxia or ischemia can result in impaired consciousness, the recovery from which is uncertain. As basal physiology NN shows brain function, it can be used as a tool for prognostication in such cases.

As our knowledge of cell and molecular biology increases, more imaging targets will become available. Even now, we are beginning to understand epigenetic regulatory mechanisms, all of which will be targetable by NN. In the coming century, we will also develop methods to restore the damaged nervous system. Neuroregeneration by regrowing axons and nerves, neurogenesis for regrowing dead or dying neurons by marshalling stem cells, either endogenous or engineered will all be part of our therapeutic armamentarium. These revolutionary therapeutic endeavors will be guided by the techniques of NN. The future is bright for NN.

About the author: Robert S. Miletich, M.D., Ph.D., FAAAS, is a scientist, clinician, teacher and administrator at the University at Buffalo. He is a professor of nuclear medicine, interim chair of the Department of Nuclear Medicine, residency program director of the Nuclear Medicine Residency and medical director of the Nuclear Medicine Technology Program. He is the author of 36 peer-reviewed papers, four reviews, nine book chapters, one book and 84 conference proceedings.