Carol E. Peyser

Neuronal loss in layers V and VI of cerebral cortex in Huntington's disease.

Neuronal loss in the cerebral cortex in Huntingtons disease (HD) has not been well documented, nor has its laminar pattern been definitively established. We therefore counted neurons in individual cortical laminae in the dorsal frontal cortex of 5 HD and 5 control autopsy brains. Significant neuronal loss (to 57% of control, P = 0.002) was found in layer VI of HD brains. These cells project principally to the thalamus, the claustrum and other regions of cerebral cortex; thus their loss is unlikely to be the result of retrograde degeneration secondary to striatal pathology. Layer V neurons were also decreased (to 71% of control, P = 0.034). Degeneration of cerebral cortical neurons may be at least partly responsible for some of the non-choreic symptoms of HD, such as dementia, irritability, apathy, and depression.

Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease.

We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography in depressed and nondepressed patients with early Huntingtons disease (HD), compared with appropriately matched controls. Caudate, putamen, and cingulate metabolism was significantly lower in patients with HD than in control subjects, independent of mood state. Orbital frontal-inferior prefrontal cortex hypometabolism, however, differentiated depressed patients from both nondepressed patients and normal controls. These findings implicate selective dysfunction of the paralimbic regions of the frontal lobes in the mood disorder of HD. The metabolic pattern is similar to that in depression associated with Parkinsons disease, suggesting that the integrity of pathways linking paralimbic frontal cortex and the basal ganglia may be integral to the normal regulation of mood.

Cognitive and motor correlates of everyday functioning in early Huntington's disease

The present study documents the prevalence of deficits in the ability to carry out a variety of activities of daily living in early Huntingtons disease (HD), along with the associated neuropsychological and motor deficits. Eighty patients with HD were assessed with the Huntingtons Disease-Activities of Daily Living Questionnaire (HD-ADL). Sixty-seven patients also completed a comprehensive assessment of cognitive and voluntary motor functioning and chorea. The latter measures were correlated with HD-ADL total score and with most HDADL items, but not with those items dealing with marital and family relationship adjustment. Findings suggest that psychomotor speed and the ability to regulate attention may be particularly important determinants of everyday functioning in mild HD. Consistent with previously reported observations, this appears to be true even after accounting for individual differences in the severity of chorea and voluntary motor impairment.

Selective loss of [3H]kainic acid and [3H]AMPA binding in layer VI of frontal cortex in Huntington's disease

Excitatory amino acid neurotoxicity has been proposed to cause the neostriatal neuronal degeneration of Huntingtons disease (HD); N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate receptors have been hypothesized to play important roles in this process. We have recently reported a loss of neurons in layer VI of the cerebral cortex in HD. Using quantitative autoradiographic methods, we have now measured NMDA, AMPA, and kainate receptor binding in the frontal cerebral cortex of the brains of controls and individuals with HD. We find no change in NMDA receptor binding but a selective decrease in kainate and AMPA receptor binding in layer VI. These data suggest that cerebral cortical neurons possessing kainate or AMPA receptors may be selectively vulnerable in individuals with HD.

Huntington's disease as a model for mood disorders : clues from neuropathology and neurochemistry

Huntingtons disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.