Robert S. Miletich

Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia

Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are known to be abnormal in schizophrenia. To test the hypothesis that these phenomena are related, we measured presynaptic dopaminergic function simultaneously with regional cerebral blood flow during the Wisconsin Card Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and matched controls. We show that the dopaminergic uptake constant Ki in the striatum was significantly higher for patients than for controls. Patients had significantly less WCST-related activation in PFC. The two parameters were strongly linked in patients, but not controls. The tight within-patient coupling of these values, with decreased PFC activation predicting exaggerated striatal 6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction may lead to dopaminergic transmission abnormalities.

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) (FSS55; n=46) or MS-nonfatigue (MSNF) (FSS44; n=20). Forty-one patients were grouped into MS-depression (MSD) (n=15) or MS-nondepression (MSND) (n=26) by interview. Higher expanded disability status scale (EDSS) scores were noted in MSF than MSNF patients (P=0.0003); EDSS scores correlated with FSS scores (rho=0.43, P=0.003). However, fatigue was present in 58% (n=29) of relapsing-remitting patients and in 52% (n=26) of patients with mild physical disability (EDSS53.5). Hamilton/Beck depression severity scores were higher in MSF than MSNF patients and correlated with FSS scores (P50.05). MSD had higher FSS scores than MSND patients (P=0.008). After controlling for EDSS, depression severity continued to correlate with FSS scores (rho=0.37, P=0.02). After controlling for depression, FSS scores no longer correlated with EDSS scores (rho=0.27, P=0.09). Thus, MSF is independent of physical disability, but is associated with depression, suggesting that common mechanisms play a role in MSF and MSD including psychological factors or brain lesions in specific neuroanatomic pathways. Further study is warranted to determine if antidepressant medications improve fatigue in MS.

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

Article abstract 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.

Where the brain appreciates the moral of a story

To identify the distributed brain regions used for appreciating the grammatical, semantic and thematic aspects of a story, regional cerebral blood flow was measured with positron emission tomography in nine normal volunteers during the reading of Aesops fables. In four conditions, subjects had to monitor the fables for font changes, grammatical errors, a semantic feature associated with a fable character, and the moral of the fable. Both right and left prefrontal cortices were consistently, but selectively, activated across the grammatical, semantic, and moral conditions. In particular, appreciating the moral of a story required activating a distributed set of brain regions in the right hemisphere which included the temporal and prefrontal cortices. These findings emphasize that story processing engages a widely distributed network of brain regions, a subset of which become preferentially active during the processing of a specific aspect of the text.

Positron emission tomographic imaging of cardiac sympathetic innervation and function.

Sites of uptake, storage, and metabolism of [18F]fluorodopamine and excretion of [18F]fluorodopamine and its metabolites were visualized using positron emission tomographic (PET) scanning after intravenous injection of the tracer into anesthetized dogs. Radioactivity was concentrated in the renal pelvis, heart, liver, spleen, salivary glands, and gall bladder. Uptake of 18F by the heart resulted in striking delineation of the left ventricular myocardium. Pretreatment with desipramine markedly decreased cardiac positron emission, consistent with dependence of the heart on neuronal uptake (uptake-1) for removal of circulating catecholamines. In reserpinized animals, cardiac positron emission was absent within 30 minutes after injection of [18F]-6-fluorodopamine, demonstrating that the emission in untreated animals was from radioactive labeling of the sympathetic storage vesicles. Decreased positron emission from denervated salivary glands confirmed that the tracer was concentrated in sympathetic neurons. Radioactivity in the gall bladder and urinary system depicted the hepatic and renal excretion of the tracer and its metabolites. Administration of tyramine or nitroprusside increased and ganglionic blockade with trimethaphan decreased the rate of loss of myocardial radioactivity. The results show that PET scanning after administration of [18F]fluorodopamine can be used to visualize sites of sympathetic innervation, follow the metabolism and renal and hepatic excretion of catecholamines, and examine cardiac sympathetic function.

Significance of hyperintense vessels on FLAIR MRI in acute stroke

Objective: To describe hyperintense vessels sign (HVS) in patients with acute stroke on fluid-attenuated inversion recovery (FLAIR) MRI and determine its clinical significance and utility. Background: Enhancement of vessels on postcontrast MRI in patients with acute stroke is considered an indicator of early brain ischemia. Recently, the FLAIR technique has shown promise in earlier and better detection of ischemic brain parenchymal lesions. Methods: Two observers retrospectively reviewed 304 MRI of patients with stroke and identified 30 patients with acute middle cerebral artery stroke and HVS on FLAIR obtained within 24 hours of symptom onset. These patients were evaluated with contrast-enhanced MRI (n = 9), MR angiography of carotid and intracranial circulation (n = 30), cerebral angiography (n = 8), transcranial Doppler (n = 17), and SPECT (n = 16). The extent of HVS was compared with final infarct size and NIH Stroke Scale score. Results: HVS on FLAIR was seen in 10% of the patients with acute stroke. HVS was associated with large vessel occlusion or severe stenosis (>90%). Intravascular enhancement on contrast MRI was observed in vessels that were hyperintense on FLAIR. Both cortical and subcortical infarcts demonstrated HVS. MR angiographic and cerebral angiographic findings of large vessel occlusion or severe stenosis (>90%), slow flow, low velocities by transcranial Doppler, and hypoperfusion on SPECT correlated with HVS. HVS was the earliest ischemic change in three patients scanned within 3 hours of ictus. Final infarct size was smaller than the area showing HVS in all patients. Conclusion: HVS on FLAIR MRI is an indicator of slow flow and early ischemia as a result of large vessel occlusion or stenosis and inadequacy of collateral circulation. HVS does not mean that infarction has occurred but indicates brain tissue at risk of infarction. It should prompt consideration of revascularization and flow augmentation strategies.

Role of fluorodeoxyglucose positron emission tomography in the diagnosis of neurosarcoidosis

A 45-year-old man developed seizures and myelopathy. MRI showed bitemporal and cervical spinal cord hyperintense lesions on T2-weighted and FLAIR images that contrast-enhanced. Initial evaluation for sarcoidosis was negative, including serum angiotensin converting enzyme (ACE) and chest X-ray. Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) revealed multiple hypermetabolic hilar and mediastinal foci and spinal cord hypermetabolism at the site of MRI abnormality. Temporal lobe MRI lesions were hypometabolic. Mediastinal lymph node biopsy was consistent with sarcoidosis. The brain, spinal cord, and chest metabolic abnormalities together with the clinical presentation were interpreted as being most consistent with sarcoidosis. FDG-PET helped target the site of biopsy that subsequently confirmed the diagnosis histologically. In patients with perplexing neurologic presentations, whole body FDG-PET can help secure a timely and minimally invasive diagnosis of neurosarcoidosis.

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.

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 Parkinsons 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.

In vivo study of nmda-sensitive glutamate receptor by 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]fluorothienylcycloexylpiperidine (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.