Regional cerebral blood flow imaging with 99mTc-bicisate SPECT in asymmetric Parkinson's disease: studies with and without chronic drug therapy.

Regional cerebral perfusion was assessed in six patients with asymmetric Parkinson's disease (PD) of mild to moderate severity and in six matched normal subjects using 99mTc-bicisate single photon emission computed tomography (SPECT). Regional activity was normalized to whole-brain activity. Each subject was studied twice, separated by 15.2 +/- 9.2 and 18.0 +/- 4.8 days in normals and PD patients, respectively. There was low intrasubject scan-rescan variability in normals, with all regions showing an average intrasubject difference in repeat studies of < 3%. In PD patients after chronic oral antiparkinsonian drugs had been withdrawn, as compared with normal subjects, there was increased perfusion in the caudate and lenticular nuclei contralateral to the worst affected extremities. This increased basal ganglia perfusion was attenuated by chronic oral therapy. The clinical relevance of these changes is indicated by the high positive correlation between various measures of clinical PD severity and the lenticular perfusion. These differences in basal ganglia perfusion measured with 99mTc-bicisate SPECT in mild to moderate, asymmetric PD may be secondary to increased metabolic demand resulting from alterations of synaptic activity.

Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients.

Fatigue is an unexplained but common and disabling symptom in MS. We assessed fatigue in 71 patients with MS and identified MS-fatigue (MSF) and MS-nonfatigue (MSNF) groups. Fatigue severity did not correlate with regional or global MRI plaque load or atrophy assessed by conventional sequences. No significant differences were noted in any MRI measures between MSF and MSNF groups. We suggest that brain MRI disease topography or severity does not explain fatigue in MS and that fatigue is likely due to mechanisms poorly characterized by conventional MRI.

In vivo study of NMDA-sensitive glutamate receptor by fluorothienylcyclohexylpiperidine [correction of fluorothienylcycloexylpiperidine], a possible ligand for positron emission tomography.

As a preliminary to positron emission tomography (PET) studies of excitatory amino acid neurotransmission, N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors of mice and rats were labelled in vivo with [3H]fluorothienylcyclohexylpiperidine [corrected] (FTCP), which binds to the phencyclidine site of the NMDA receptor. After intravenous injection, the half-life of clearance of authentic FTCP from blood was 4.2 min in mice, 12 min in rats and 45 min in a rhesus monkey. In rodent brain, the specific binding of [3H]FTCP, 10 min after intravenous injection, was 10-20% of the total binding and no regional differences were observed. However, if animals were treated with NMDA intraperitoneally (0.68 mmol/kg), 10 min before injection of [3H]FTCP, a three- to five-fold increase in specific binding was observed in hippocampus, cerebral cortex and striatum but not in cerebellum. Thus, specific binding of [3H]FTCP in vivo revealed the physiological status of the NMDA receptor; in fact, preliminary PET studies with [18F]FTCP in monkeys indicated increased binding after activation of NMDA receptors. These data suggest that PET with [18F]FTCP can be a tool to evaluate physiological or pathological modifications of the function of NMDA receptors.

6-[18F]fluoro-L-dihydroxyphenylalanine metabolism and positron emission tomography after catechol-O-methyltransferase inhibition in normal and hemiparkinsonian monkeys.

Increased and sustained central delivery of L-dihydroxyphenylalanine (L-DOPA) is a desirable therapeutic strategy in Parkinson's disease. We investigated the effects of peripheral catechol-O-methyltransferase (COMT) inhibition, by the non-toxic drug nitecapone on the metabolism of 6-[18F]fluoro-L-dihydroxyphenylalanine (6FD) and on its positron emission tomography (PET) imaging in non-human primates. Nitecapone produced a dose-dependent inhibition in the formation of 3-O-methyl-6-[18F]fluorodihydroxyphenylalanine (OMFD). This inhibition of OMFD formation was attended by increased production of other metabolites, in particular 6-[18F]fluorodopamine (6FDA), 6-[18F]fluorodihydroxyphenylacetic acid (FDOPAC), 6-[18F]fluorohomovanillic acid (FHVA) and [18F]-sulfated conjugates (FSC). Although nitecapone had no effect on plasma 6FD pharmacokinetics, high-dose nitecapone increased contrast of cerebral 18F uptake and retention between regions with high (striatum) versus sparse (parieto-occipital lobes) dopaminergic innervation. 18F uptake contrast was also improved between structures known to possess an intermediate dopaminergic innervation, including the upper brainstem, frontal and temporal lobes, versus sparsely innervated regions. This increased contrast was secondary to decreased activity in sparsely innervated structures and not to increased activity in highly innervated structures. Contrast was correlated inversely with the plasma OMFD/6FD concentration ratio, OMFD being the main 6FD metabolite which can cross the blood brain barrier. We conclude that nitecapone is an effective inhibitor of COMT in non-human primates. This inhibition results in increased 6FD flux through other catabolic pathways. Because of decreased OMFD formation, however, COMT inhibition improves the specificity of 6FD-PET and facilitates in-vivo detection of a wide range of dopaminergic innervation densities in cerebral structures.

Angioplasty and stenting of basilar artery stenosis: technical case report.

OBJECTIVE AND IMPORTANCE: Symptomatic basilar artery stenosis has a poor prognosis. Treatment options are limited. Surgical bypasses are technically demanding and of no proven benefit. Percutaneous angioplasty is associated with a significant complication rate, because of intraplaque dissection, restenosis secondary to vessel recoil, and embolic phenomena. A new generation of intravascular stents that are flexible enough to navigate the tortuosities of the vertebral artery may provide a new therapeutic approach. We report a case of basilar artery stenosis that was treated using stent-assisted angioplasty. CLINICAL PRESENTATION: A 56-year-old woman experienced a vertebrobasilar ischemic stroke, from which she recovered. Magnetic resonance angiography revealed severe proximal basilar artery stenosis. Brain Neurolite-single-photon emission computed tomographic scans revealed significantly decreased perfusion of the brainstem. Endovascular intra-arterial pressure measurements revealed a 35-mm Hg gradient across the lesion. INTERVENTION: The patient underwent uncomplicated angioplasty and stenting of the proximal basilar artery, with excellent angiographic results. CONCLUSION: The availability of new flexible intravascular stents, allowing access to tortuous proximal intracranial vessels, provides a new therapeutic approach for patients with basilar artery stenosis. Long-term follow-up monitoring is required to assess the durability of this approach.

Positron emission tomography of pituitary macroadenomas: hormone production and effects of therapies.

Positron emission tomography with [18F]fluorodeoxyglucose (FDG) was carried out in 24 patients with pituitary macroadenomas (32 studies) to assess the glucose utilization of these tumors in vivo. The adenoma metabolic index, which is the ratio of FDG uptake of tumor to a whole brain slice, was calculated. Comparisons were made between tumor uptake of FDG and hormone secretion and response to therapies. In each positron emission tomography study, the macroadenoma could be easily identified visually as an area of increased FDG uptake near the region of the sella. FDG uptakes were highest for nonfunctional adenomas, and the prolactin, growth hormone, and thyroid-stimulating hormone-producing groups displayed similar levels of glucose metabolism. The adenoma metabolic index for all tumors averaged 1.3, ranging from 0.3 for a thyroid-stimulating hormone adenoma to 3.5 for a nonfunctional tumor. Tumors did not exhibit metabolic rates that could characterize the type of hormone produced. Recurrent macroadenomas displayed metabolism similar to tumors not operated on, whereas irradiated adenomas showed lower glucose uptake than nonirradiated tumors. Drug therapy with bromocriptine or the long-acting somatostatin analogue octreotide also decreased the glucose utilization of the tumor. There was no correlation between the amount of hormone produced and the adenoma metabolic index when a group of tumors was analyzed. Patients scanned more than once, however, demonstrated changes in hormone levels that changed or did not change in parallel with tumor metabolism. Thus, positron emission tomography offers the potential capability for predicting and defining the growth of pituitary adenomas. This may be of particular value when plasma hormone assays and conventional imaging techniques prove inadequate for monitoring patient response to therapy.

Positron emission tomography in the detection of malignant degeneration of low-grade gliomas.

The management of low-grade gliomas represents a challenge to the physician as a significant proportion may undergo malignant degeneration to a high-grade tumor. We present the positron emission tomography (PET) scans, using [18F] fluorodeoxyglucose (FDG), of 12 patients who have histological and/or clinical evidence of malignant degeneration of a low-grade glioma. Each scan displays a focal area of hypermetabolism similar to that of malignant gliomas which arise de novo. Three patients also underwent PET scanning prior to malignant degeneration. When the initial scan is compared with the postmalignant degeneration study, a difference in tumoral glucose uptake can be recognized. A region previously shown to be hypometabolic develops focal hypermetabolism as malignant changes evolve. This study displays the utility of FDG-PET in the evaluation of malignant degeneration of low-grade gliomas. The knowledge that a neoplasm has altered its biological behavior may influence subsequent therapeutic options. If these findings can be confirmed in larger series and by other investigators, it is possible that FDG-PET may be adopted as one of the diagnostic tools for guiding the management of low-grade gliomas.

Improved cerebral perfusion after stenting of a petrous carotid stenosis: technical case report.

OBJECTIVE AND IMPORTANCE: Atherosclerotic occlusive disease of the intracranial vasculature is associated with increased risk of systemic vascular occlusive disease and stroke. Therapeutic options have included anticoagulation therapy, antiplatelet therapy, or, in a limited number of patients, extracranial-intracranial vascular bypass procedures. We report a patient who had improved cerebral perfusion with silent watershed zone infarctions after endovascular stenting of a severe petrous segment carotid stenosis. CLINICAL PRESENTATION: A 73-year-old man with severe coronary artery disease and unstable angina was referred for treatment of a 90% right petrous carotid artery stenosis before coronary artery bypass grafting. A brain single-photon emission computed tomographic scan using 99mTc-bicisate revealed diminished perfusion throughout the right internal carotid artery territory, particularly in posterior watershed zones. TECHNIQUE: The patient underwent transfemoral placement of a 7-French introducer sheath, followed by a 7-French guide catheter. Urokinase (225,000 U) was infused through a microcatheter placed proximal to the lesion. No changes were noted in lesion morphology after this infusion. A microguidewire was navigated across the lesion. Subsequent balloon angioplasty with a coronary artery balloon was performed twice, followed by placement of a 4- x 12-mm coronary stent. CONCLUSION: Selective internal carotid artery angiography after stenting revealed markedly improved flow. A brain 99mTc-bicisate single-photon emission computed tomographic scan performed within 24 hours of stent placement, revealed significantly improved perfusion within the right internal carotid artery territory. Two perfusion voids suggestive of embolic stroke were noted; both were clinically silent. The patient had uncomplicated coronary artery bypass grafting 72 hours later. Five months postoperatively, he remains at home, living independently and with intact neurological function. Intracranial stenting for severe atherosclerotic stenosis is technically possible. However, its ultimate clinical role remains to be determined.

Long-term evaluation of hemiparkinsonian monkeys after adrenal autografting or cavitation alone.

Autografts of adrenal medulla were implanted into preformed cavities in the caudate nuclei of four rhesus monkeys with hemiparkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Five other hemiparkinsonian monkeys underwent caudate cavitation, but received no tissue implant. All of the animals had marked bradykinesia of the affected arm and stable apomorphine-induced turning before cavitation or implantation. Moderate behavioral recovery was seen in all five monkeys with cavitation and two of the three monkey with long-term adrenal autografts (the fourth adrenal recipient was sacrificed 10 days after grafting). The improvement occurred months after the procedure and was not as early or as complete as that seen after fetal dopaminergic grafts. Surviving adrenal tissue was found only in the animal that showed no behavioral recovery. The other two adrenal autograft recipients (with no surviving adrenal medulla) and all of the animals with cavitation had ingrowth of dopaminergic fibers from the area olfactoria and nucleus accumbens into the caudate, oriented toward the cavity. These findings show that the mechanism of improvement after adrenal medullary implants for parkinsonism is not dopamine secretion by chromaffin cells, but may be related to the sprouted host fibers. The results also indicate that the limited recovery after adrenal implants in parkinsonian patients may be a result of the cavitation, and not necessarily the result of tissue implantation.

High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis.

The authors study brain regional glucose metabolism prospectively in multiple sclerosis (MS) using high-resolution 2-[18-F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in 25 MS patients of the Dent Neurologic Institute compared with 6 healthy subjects. Glucose metabolism is measured in 20 regions of interest using a line-profile technique. Compared with control subjects, a 9% reduction in total brain glucose metabolism is noted in MS patients (p < 0.05). Hypometabolism is widespread, including the cerebral cortex, subcortical nuclei, supratentorial white matter, and infratentorial structures. This reduction represents absolute regional decreases ranging from 3% to 18%. The most dramatic absolute reductions occur in the superior mesial frontal cortex, superior dorsolateral frontal cortex, mesial occipital cortex, lateral occipital cortex, deep inferior parietal white matter, and pons. The regional hypometabolism in the superior mesial frontal cortex and superior dorsolateral frontal cortex is statistically significant (p < 0.05), whereas the changes in the mesial occipital cortex (p = 0.07) and the lateral occipital cortex (p = 0.09) approach significance. The authors' findings suggest that widespread cerebral dysfunction occurs in MS, and that diaschisis or neuronal system disconnection resulting from white matter disease plays a major role. Cortical gray matter hypometabolism may also reflect direct MS involvement. The quantitative cerebral abnormalities detected by FDG PET may serve as a marker of disease activity in understanding the pathophysiological expression and therapeutic response of MS.

Neuropsychological and glucose metabolic profiles in asymmetric Parkinson's disease.

Patients with predominantly unilateral parkinsonian signs may provide a unique opportunity to evaluate the cerebral representation of cognitive functions characteristically affected in idiopathic Parkinson's disease. Twenty hemiparkinsonian patients (ten left and ten right) and 10 healthy controls, matched for age and education, were studied with neuropsychological tests and positron emission tomography. Both right and left hemiparkinsonians evidenced impairments in visuospatial and verbal episodic memory function, but had no deficits in executive abilities, compared to controls. None of the neuropsychological test scores distinguished right from left hemiparkinsonians. Glucose metabolic profiles were identical for the three groups in all cortical areas assessed; in the subcortex however, lenticular hypermetabolism contralateral to the predominant side of motor involvement was evident in the left hemiparkinsonian group. Correlational analysis revealed that higher glucose metabolic rates in the basal ganglia of these hemiparkinsonians were associated with lower visuospatial test scores. In frontal and parietal cortex, decreasing glucose metabolism was positively associated with neurobehavioral function; in temporal cortex, measures of attention and memory decreased with increasing glucose metabolic rates.

Cerebral metabolic changes in Alzheimer's disease: neurobehavioral patterns.

Regional cerebral glucose metabolism was surveyed in 37 Alzheimer's disease (AD) patients and 21 normal controls using positron emission tomography. Where possible, brain regions were specified according to their neurobehavioral function rather than as anatomically demarcated structures. Absolute metabolic values revealed significant differences (p < 0.05) between AD patients and controls for whole brain and the more superior supratentorial brain slices. Normalized values (region/brain stem) showed the most striking declines (p < 0.001) in the association cortex (heteromodal region -21%; unimodal region -19%) and the primary sensory-motor cortex (-13%), with motor, auditory, and visual areas more affected than somatosensory areas. Limbic and paralimbic systems were equally affected (-14%; -11%; p < 0.001). Thalamus, striatum, cerebellum and brain stem were minimally or not affected. Neurobehaviorally defined hypometabolic regions largely parallel affected areas noted in anatomic and previous metabolic studies, with the possible exception of metabolic deficits in the primary sensory-motor complex. Conceivably, brain areas unaffected morphologically by the pathophysiological processes of AD may become dysfunctional due to a disruption of connectivity between regions.

Changes in cerebral glucose metabolism with normal aging.

The pattern of changes in cerebral glucose metabolism occurring with normal aging has been unclear. Advances in imaging technology, such as improved resolution and anatomical referencing, allow for more precise regional measurement than previously possible. This study explored cerebral glucose metabolism in 17 normal controls ranging in age from 20 to 74 years. High resolution PET scanning, with MRI-based regions of interest correcting for partial volume and atrophy effects, revealed a linear association between advancing age and declining cerebral glucose metabolism. The decline averaged 8% per decade for the whole brain. Changes were most pronounced in limbic structures, and could be implicated in age-associated memory loss.

MRI detects acute degeneration of the nigrostriatal dopamine system after MPTP exposure in hemiparkinsonian monkeys.

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause an acute chemical toxicity resulting in a parkinsonian state in humans and nonhuman primates. We wished to assess whether the toxicity from MPTP is associated with changes on magnetic resonance images of brain structures containing dopamine neuronal processes or with disrupture of the blood-brain barrier. Normal rhesus monkeys and monkeys at various times after being subjected to unilateral intracarotid injection of MPTP (0.4 mg/kg) were studied with magnetic resonance imaging using T1- and T2-weighted spin-echo and gradient-echo sequences. Disrupture of the blood-brain barrier was assessed also with magnetic resonance imaging after administration of gadolinium-diethylenetriamine pentaacetic acid. Parkinsonian symptoms contralateral to the infused carotid usually appeared within 1 day after MPTP exposure, reaching their peak severity by 7 days, when all monkeys showed clear clinical abnormalities. Magnetic resonance imaging changes developed in concomitance with the clinical signs and were characterized by increased signal intensity on T2-weighted images as well as decreased intensity on T1-weighted images of the ipsilateral caudate and putamen. T2 hyperintensity was also present just dorsal to the pars compacta of the substantia nigra, in the region of the proximal nigrostriatal tract. All magnetic resonance imaging changes dissipated in the next 2 weeks. There were no abnormalities at any time in the globus pallidus, nucleus accumbens, and other structures innervated by the mesocorticolimbic dopamine system. After MPTP exposure, there was no evidence of blood-brain barrier disrupture, suggesting that vasogenic edema was an unlikely factor in the production of the observed abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of iron and ferritin in MR imaging of the brain: a study in primates at different field strengths.

The authors measured in vivo signal intensity on magnetic resonance (MR) images and postmortem iron concentrations in the brains of three young and two old rhesus monkeys. T2-weighted MR imaging was done at 0.5, 1.5, 2.0, and 4.7 T. Relative assessment of iron concentration was made from the optical density of brain sections stained with the Perls' method intensified with diaminobenzidine. MR imaging and optical density measurements were made in the centrum semiovale (white matter) and in four gray matter areas: the insular cortex, caudate nucleus, putamen, and globus pallidus, the latter three of which accumulate significant iron deposits with age. High optical density and decreased signal intensity were found in these areas, and the inverse correlation between gray matter/white matter signal ratio and optical density was in good agreement with the theory of T2 shortening caused by diffusion of water through magnetic inhomogeneities. However, the dependence of T2 shortening on field strength was not quadratic, as expected for paramagnetic iron, but instead showed a marked leveling off at higher field strengths. This magnetic "saturation" is explainable by antiferromagnetism and superparamagnetism of the ferritin core and has been observed in ferritin solutions at low temperatures. Similar observations at body temperature are needed before the iron-ferritin explanation for T2 shortening can be considered proved.

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability.

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS>/=5; n=46) or MS-nonfatigue (MSNF) (FSS

Kinetic analysis of muscarinic receptors in human brain and salivary gland in vivo.

Previous studies in rats have suggested that the muscarinic acetylcholine receptor (mAChR) antagonist (S)-3-quinuclidinyl-(S)-4-[123I]iodobenzilate [(SS)-IQNB] may be useful for the in vivo evaluation of mAChRs in humans as a control for the higher-affinity compound (RR)-IQNB. We have directly tested this hypothesis and examined the distribution of mAChRs in brain regions and parotid glands of healthy human volunteers in vivo using (RR)- and (SS)-IQNB (relatively high- and low-affinity antagonists, respectively), planar imaging, and pharmacokinetic analysis. This is the first in vivo study of mAChRs in humans that has employed stereoisomeric ligands and metabolic analysis to determine specific receptor binding. We observed that (SS)-IQNB showed much faster clearance from blood than (RR)-IQNB and different metabolite profiles. Also, the transport kinetics of the enantiomers were different. The estimated binding potential (approximately Bmax/Kd) of (RR)-IQNB was highest in two cortical regions, intermediate in parotid gland, and lowest in cerebellum. The aggregate results show that in humans (SS)-IQNB does not act as an ideal general probe to measure the nonspecific IQNB distribution. However, (RR)-IQNB does appear to have value when used for studies of human brain mAChRs.