Widespread functional effects of discrete thalamic infarction.

In order to investigate functional effects of various thalamic structures on metabolism in remote, morphologically intact cerebral regions, we used positron emission tomography of (18F)-2-fluoro-2-deoxy-D-glucose to study regional cerebral metabolic rates of glucose (rCMRGlu) in 11 patients with chronic unilateral or bilateral infarcts strictly confined to the thalamus. Patients were grouped according to computed tomographic scans showing anterior (three), medial (four), or posterior (four) lesions. Compared with a matched group of 11 healthy subjects (hemispheric CMRGlu 35.2 +/- 3.49 mumol/100 g per minute), glucose metabolism was significantly lower in the hemisphere ipsilateral to the infarction (31.2 +/- 2.97 mumol/100 g per minute). Patients with bilateral infarcts had lower hemispheric CMRGlu (29.9 +/- 2.74 mumol/100 g per minute) than those with unilateral lesions (32.2 +/- 2.97 mumol/100 g per minute). Depending on infarct location within the thalamus, there was differential depression of rCMRGlu, with the largest effects on frontal and occipital areas in medial infarctions. Except for ipsilateral thalamic deactivation, metabolic patterns with anterior thalamic infarcts were close to normal, while posterior infarcts mostly depressed rCMRGlu in the visual and in the inferior limbic cortex. Cerebellar metabolic rates were within normal limits in most cases. These patterns of regional cerebral deactivation may be related to categories of thalamic projections--intrathalamic, to limbic system and basal ganglia, diffuse to most cortical areas, and specific to defined neocortical areas. Even small brain lesions may have widespread functional sequelae, potentially demonstrable by positron emission tomography.

Positron emission tomography findings relevant to neurosurgery for epilepsy.

Using the 2-[F-18]fluorodeoxyglucose method, 213 positron emission tomographic (PET) studies of local brain glucose metabolism (CMRglu) were performed in 124 patients with various forms of epilepsy. Interictal PET scans of primary epileptics typically showed some global metabolic depression and decreased functional activity of insular, basal and anterior temporal cortex. Epilepsia partialis continua Kozevnikov was characterized by hypo- or hyper-metabolism of perirolandic cortex. Tuberous sclerosis was distinguished by neocortical foci of significantly decreased glucose consumption. Even in the interictal resting state, with regard to sensitivity (greater than 90%) and accuracy of focus localization. PET was superior to other diagnostic methods in typical temporal lobe epilepsy. Averaging 23% below normal CMRglu, the majority of hypometabolic foci were found in mesial temporal structures. Improved distinction between the epileptogenic area and the surrounding tissue showing comparatively normal functional responsiveness, was achieved by psychophysical activation using emotional speech or continuous visual recognition during PET scanning. In patients who had undergone total cerebral hemispherectomy because of uncontrolled epilepsy, remarkable recruitment of association areas was observed on both motor and speech activation.

Regional cerebral blood flow measurement with intravenous [15O]water bolus and [18F]fluoromethane inhalation.

In 20 patients with ischemic cerebrovascular disease, classic migraine, or angiomas, we compared paired dynamic positron emission tomographic measurements of regional cerebral blood flow using both [15O]water and [18F]fluoromethane as tracers. Cerebral blood flow was also determined according to the autoradiographic technique with a bolus injection of [15O]water. There were reasonable overall correlations between dynamic [15O]water and [18F]fluoromethane values for cerebral blood flow (r = 0.82) and between dynamic and autoradiographic [15O]water values for cerebral blood flow (r = 0.83). We found a close correspondence between abnormal pathologic findings and visually evaluated cerebral blood flow tomograms obtained with the two tracers. On average, dynamic [15O]water cerebral blood flow was 6% lower than that measured with [18F]fluoromethane. There also was a general trend toward a greater underestimation with [15O]water in high-flow areas, particularly in hyperemic areas, probably due to incomplete first-pass extraction of [15O]water. Underestimation was not detected in low-flow areas or in the cerebellum. Absolute cerebral blood flow values were less closely correlated between tracers and techniques than cerebral blood flow patterns. The variability of the relation between absolute flow values was probably caused by confounding effects of the variation in the circulatory delay time. The autoradiographic technique was most sensitive to this type error.

Positron emission tomography findings in dementia disorders: contributions to differential diagnosis and objectivizing of therapeutic effects.

At present, positron emission tomography (PET) is the only technology affording the quantitative three-dimensional imaging of various aspects of brain function. Since glucose is the dominant substrate of the brain's energy metabolism, studies of glucose metabolism by PET of 2(18F)-fluoro-2-deoxy-D-glucose (FDG) are widely applied for investigating the participation of various brain systems in simple or complex stimulations and tasks. In focal or diffuse disorders of the brain, functional impairment of affected or inactivated brain regions is a reproducible finding. While glucose metabolism is decreased slightly with age in a regionally different degree, in most types of dementia severe changes of glucose metabolism are observed. Degenerative dementia of the Alzheimer type is characterized by a metabolic disturbance most prominent in the parietooccipito-temporal association cortex and later in the frontal lobe, while primary cortical areas, basal ganglia, thalamus, and cerebellum are not affected. By this typical pattern Alzheimer disease can be differentiated from other dementia syndromes, as e.g. Pick's disease (with the metabolic depression most prominent in the frontal and temporal lobe), multi infarct dementia (with multiple focal metabolic defects), and Huntington's chorea (with metabolic disturbance in the neostriatum). In demented patients PET studies can also be applied to the quantification of treatment effects on disturbed metabolism. Such studies demonstrated an equalization of metabolic heterogeneities in patients responding to muscarinergic cholinagonists and diffuse increase of metabolism during treatment with piracetam. The therapeutic relevance of such metabolic effects, however, must be proved in controlled clinical trials.

Effect of piracetam on cerebral glucose metabolism in Alzheimer's disease as measured by positron emission tomography.

The effect of piracetam (a putative enhancer of cerebral metabolism) on regional CMRGlu was studied by positron emission tomography of 2[18F]-fluoro-2-deoxy-D-glucose in nine patients with Alzheimer's disease, and in seven cases with multiinfarct dementia or unclassified dementia. In Alzheimer's disease, i.v. administration of piracetam, 6 g b.i.d. for 2 weeks, significantly improved rCMRGlu in most cortical areas, whereas no effect on CMRGlu of the drug was observed in the multiinfarct dementia/unclassified dementia groups. These results lend further support to the notion that adjuvant piracetam treatment is of benefit in Alzheimer's disease. They may also indicate that the typical metabolic depression in Alzheimer's disease is caused by complex interaction of disturbed transmitter and cellular function rather than by a specific deficit in the cholinergic system alone.

PET measurement of D2 and S2 receptor binding of 3-N-[( 2'-18F]fluoroethyl)spiperone in baboon brain.

The regional pharmacokinetic behavior in baboon brain of 18F-fluoroethyl- and 18F-fluoropropylspiperone (18FESP, 18FPSP) at specific activities greater than or equal to 1000 Ci/mmol was studied with PET. Four hours after injection of 5-10 mCi 18FESP, uptake in striatum was 0.048% +/- 0.005% of injected dose per cm3, which is almost the same as with 18F- and 11C-methylspiperone. While 18FPSP was taken up in much smaller amounts than 18FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, 18FESP seems to be better suited for PET. Furthermore, relative binding to S2 receptors was much smaller for FESP: competing cold S2 antagonists (ritanserin, ketanserin) did not alter 18FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%-20%. With coinjection of increasing amounts of cold FESP, saturation of 18FESP binding to striatum occurred at doses exceeding 10 micrograms per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the 18FESP plasma concentration time curve and the dynamic uptake data, k3 of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k3 on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of Bmax yielded a D2 receptor density of only 6 pmol per cm3 in baboon striatum.

Positron emission tomography in depression research: principles--results--perspectives.

At present, PET is the only technology affording the quantitative, three-dimensional imaging of various aspects of brain function. In the few PET studies of mood disorders performed so far, usually cerebral glucose metabolism was investigated by the fluorodeoxyglucose method. Its largest individual diagnostic potential was demonstrated in certain forms of organic depression, while metabolic abnormalities in major unipolar and bipolar depression were more subtle--albeit significantly different. Other PET tracers for investigation of transmitter systems are available, but have not been systematically applied in depression research.