Coexistence of Huntington's disease and familial amyotrophic lateral sclerosis: case presentation.

We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington's disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characteristic of Alzheimer's disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke's columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members.

Synthesis and biological evaluation in mice of (2-[11C]methoxy)-6',7'-dihydrorotenol, a second generation rotenoid for marking mitochondrial complex I activity.

Evidence has accumulated suggesting that impairment of the function of the complexes of the mitochondrial respiratory chain might be involved in the pathology of neurological diseases including Parkinson's and Huntington's diseases. Recently we reported the synthesis of (2-[11C]methoxy)rotenone ([11C]ROT) as a tool for in vivo studies of complex I. In an effort to develop a complex I imaging radiotracer which might be easier to synthesize and less likely to be metabolized, we prepared (2-[11C]methoxy)-6',7'-dihydrorotenol ([11C]DHROT). The radiotracer was synthesized by [11C]methylation of 2-O-desmethyl-6',7'-dihydrorotenol under basic [11C]alkylation conditions. (2-[11C]Methoxy)-6',7'-dihydrorotenol was produced in 30-35% radiochemical yields (decay corrected), with synthesis times shorter than 35 min. Radiochemical purities were over 95% and specific activities averaged 1000 Ci/mmol. The brain distributions of [11C]ROT and [11C]DHROT were investigated in mice after intravenous injections. For both radiotracers, distribution of radioactivity was similar in all brain regions examined. However, significantly higher uptake was observed with [11C]DHROT than with [11C]ROT, indicating that the alterations introduced in the structure of rotenone during the design of [11C]DHROT resulted in a tracer with greater brain barrier permeability.

Evidence for transient perinatal glutamatergic innervation of globus pallidus.

There is no known glutamatergic innervation of globus pallidus (GP) in adult mammals, but we report that during postnatal development of the GP there are large, transient increases in both presynaptic high-affinity glutamate uptake and postsynaptic Na+-independent glutamate receptor binding. These glutamatergic markers increase rapidly in rat GP after birth and then decrease to adult levels over a period of weeks. A similar developmental pattern of pallidal glutamate binding was found in human brains. In contrast, binding in rat caudate-putamen (CPu) increases after birth, reaches a peak, and remains constant into adulthood. The results suggest that a glutamatergic pathway transiently innervates the globus pallidus during the perinatal period. Because glutamate is an excitotoxin, this pathway may account, in part, for the basal ganglia damage seen in some forms of cerebral palsy after perinatal hypoxia/ischemia.