technetium-tc-99m-exametazime and Nerve-Degeneration

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently collect an abundance of physiological information, including the degree and regional extent of blood-CNS barrier permeability, in a preclinical model of neurodegeneration.

Topics: Amyotrophic Lateral Sclerosis; Animals; Blood Volume; Blood-Brain Barrier; Cerebrovascular Circulation; Chlorides; Disease Models, Animal; Drug Delivery Systems; Female; Humans; Immunoglobulin G; Mice; Mice, Mutant Strains; Mice, Transgenic; Nerve Degeneration; Protein Transport; Radionuclide Imaging; Radiopharmaceuticals; Rubidium; Rubidium Radioisotopes; Superoxide Dismutase; Technetium Tc 99m Exametazime; Tissue Distribution

Progressive clumsiness developed in the right hand of a 33-year-old man, became bilateral and evolved very slowly for ten years. Another neurological deficit was restricted to a slight impairment of superficial sensations. Magnetic resonance imaging verified an atrophy of bilateral parietal lobes. The cerebral blood flow was markedly decreased in the atrophic area. Pure clumsiness of a very slowly progressive course due to parietal atrophy has never been reported in such a young adult. This clinical picture may suggest another variety of degenerative process.

Topics: Adult; Apraxias; Atrophy; Brain; Cerebrovascular Circulation; Disease Progression; Hand; Humans; Magnetic Resonance Imaging; Male; Motor Cortex; Nerve Degeneration; Organotechnetium Compounds; Oximes; Parietal Lobe; Radionuclide Imaging; Technetium Tc 99m Exametazime

We report a case of sporadic olivopontocerebellar atrophy (OPCA) with marked laterality of cerebellar atrophy and degenerative changes in the corticopontine tract. A 35-year-old man was admitted to our hospital for evaluation of titubation, gait disturbance, dysarthria, and urinary and fecal incontinence. Neurological examination showed a wide based gait, slurred speech, truncal ataxia, slightly saccadic ocular movement, and finger-to-nose incoordination, greater on the right than the left. Deep tendon reflexes were hyperactive and preserved with the right side greater than the left. Bilateral Babinski signs were present, and the patient had neurogenic bladder without orthostatic hypotension. Cranial MRI showed atrophy of the cerebellum with right dominance and of the pons. On T2- and PD-weighted images, high-intensity areas were detected at the left internal capsule, crus cerebri and ventral pons. These findings were compatible with the right dominance of the clinical symptoms. The high intensity area detected at the posterior internal capsule was more extensive than that seen in patients with motor neuron disease. This finding may coincide with the degenerative changes in the corticopontine tract. Moreover, 99mTc-HMPAO-SPECT showed the crossed cerebello-cerebral diaschisis (CCCD) pattern, which indicates the decreased CBF in the right cerebellar hemisphere and the left frontal lobe. These findings may reflect degenerative changes in the corticopontine tract in OPCA.

Topics: Adult; Cerebral Cortex; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Nerve Degeneration; Olivopontocerebellar Atrophies; Organotechnetium Compounds; Oximes; Pons; Radiography; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

A case of intractable seizures, originating in the motor cortex, was successfully treated with excision of the seizure focus after precise location of the focus on depth electrode recordings. The depth electrode was placed stereotactically with coordinates from xenon-enhanced CT images. Prior attempts at treating the seizures with ablation of seizure foci had resulted in disappearance of seizure activity on electrocorticography study without cessation of clinical seizures.

Topics: Brain Mapping; Child; Dominance, Cerebral; Epilepsies, Partial; Female; Gliosis; Humans; Motor Cortex; Nerve Degeneration; Organotechnetium Compounds; Oximes; Radiographic Image Enhancement; Regional Blood Flow; Stereotaxic Techniques; Technetium Tc 99m Exametazime; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Xenon

Topics: Basal Ganglia; Basal Ganglia Diseases; Cerebral Cortex; Diagnosis, Differential; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Nerve Degeneration; Organotechnetium Compounds; Oximes; Parietal Lobe; Parkinson Disease; Regional Blood Flow; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon