technetium-tc-99m-exametazime and Amyotrophic-Lateral-Sclerosis

Three cases of rapid onset neuropsychological frontal dementia preceded the development of sporadic amyotrophic lateral sclerosis by 12 to 24 months. HmPAO Tc99m scintigraphy demonstrated hypoactivity in the cortex, predominantly in the frontal region. Three hypotheses are discussed: 1) coincidence between two degenerative diseases, Alzheimer's disease or Pick's disease and ALS; 2) an amyotrophic form of Creutzfeld Jakob disease; 3) pre-senile dementia associated with a motoneuron disease, a clinical pathology entity recently described by Mitzuyama.

Topics: Aged; Amyotrophic Lateral Sclerosis; Dementia; Frontal Lobe; Humans; Male; Organotechnetium Compounds; Oximes; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

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

A prospective psychometric study was conducted in 16 patients who recently developed classic sporadic amyotrophic lateral sclerosis and had no signs of anxiety or depression. Tests included PM38, MMS, Rey word and Rey image tests, span, Stroop test, verbal fluency, Wisconsin test and London Tower test coupled with 99m Tc HMPAO tomography. Results demonstrated that the patients had no intellectual degradation nor visual constructive disorders but had disturbed verbal and visual memory with a reduced verbal fluency (particular bulbar forms), perseverance errors on the Wisconsin test (half of the cases) and an increased number of movements in the London Tower test. These disorders were moderate with no clinical impact and variable (the neuropsycological examination was normal in 4/16 patients). 99m Tc HMPAO tomography was normal in 4 cases, showed slight rolandic hypoperfusion in 6 and extensive hypoperfusion outside the motor zone in 2. Visual analysis of the 99m Tc HMPAO images did not reveal any clinico-metabolic correlations.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Brain; Cognition Disorders; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Prospective Studies; Psychometrics; Radiopharmaceuticals; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Atrophy; Brain; Family Health; Frontal Lobe; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Parietal Lobe; Technetium Tc 99m Exametazime; Thalamus; Tomography, Emission-Computed, Single-Photon

We investigated regional cerebral blood flow (rCBF) using the [99mTc]-d,l-HMPAO technique with brain dedicated high resolution single photon emission computer tomography (SPECT) in 14 consecutive patients with amyotrophic lateral sclerosis (ALS), median age 62 years (45-77). Global CBF, expressed in % relative to the cerebellum, was significantly lower (P less than 0.05) in the ALS group (80.5 +/- 6.7%) than in the control group of 14 age-matched healthy volunteers (87.0 +/- 7.5%). Eight patients (57%) had abnormal rCBF distribution maps with reduced flow, primarily in the frontal lobes. Three of the 8 patients with abnormal rCBF had mild to moderate dementia and another one had mild aphasia. None of the patients with normal rCBF distribution maps had dementia. In the group of ALS patients as a whole rCBF was significantly reduced in the frontal cortex, the hippocampus, and the central white matter. We conclude that reduced rCBF, primarily in the frontal lobes, is a frequent finding in patients with ALS. The decreased rCBF may be associated with cognitive deficits and is most likely caused by neuronal degeneration and reduced metabolic needs.

Topics: Aged; Amyotrophic Lateral Sclerosis; Central Nervous System Diseases; Cerebrovascular Circulation; Female; Humans; Male; Middle Aged; Organotechnetium Compounds; Oximes; Technetium Tc 99m Exametazime; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Xenon Radioisotopes