Edward D. Bird

Neuropathological classification of Huntington's disease.

In postmortem brain specimens from 163 clinically diagnosed cases of Huntingtons disease (HD) the striatum exhibited marked variation in the severity of neuropathological involvement. A system for grading this severity was established by macroscopic and microscopic criteria, resulting in five grades (0–4) designated in ascending order of severity. The grade correlates closely with the extent of clinical disability as assessed by a rating scale. In five cases of clinically diagnosed HD there were no discernible neuropathological abnormalities (grade 0), suggesting that the anatomical changes lag behind the development of clinical abnormalities. In eight cases, neuropathological changes could only be recognized microscopically (grade 1). The earliest changes were seen in the medial paraventricular portions of the caudate nucleus (CN), in the tail of the CN, and in the dorsal part of the putamen. Counts of neurons in the CN reveal that 50% are lost in grade 1 and that 95% are lost in grade 4; astrocytes are greatly increased in grades 2–4. These studies indicate that analyses of the CN in grade 4 would reflect mainly its astrocytic composition with a component of remote neurons projecting to the striatum. Because of the relative preservation of the lateral half of the head of the CN in grades 1–2, these regions would reflect early cellular and biochemical changes in HD.

Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease

We have previously found that a biochemically distinct subset of neurons, containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-4), is selectively resistant to the degenerative process that affects the striatum in Hunting-tons disease (HD). We report the morphologic and histochemical characteristics of these striatal neurons and their distribution with respect to the histochemical compartments as defined by acetylcholinesterase (AChE) activity. Sections of striatum were stained histochemically for NADPH-d and AChE and immunocytochemically for somatostatin and neuropeptide Y-like immunoreactivity. The diaphorase end-product was contained within medium-sized neurons which corresponded morphologically to a category of aspiny interneurons. Combined techniques showed that NADPH-d, somatostatin, and neuropeptide Y coexisted within the same neurons in controls and patients with HD. The density of these neurons was greater in the ventral putamen and the nucleus accumbens than in the remainder of the striatum. The distinctive AChE pattern of high and low enzyme activity was altered in HD. The AChE-rich matrix zone was markedly reduced in size, while the total area of zones of low enzyme activity was not different from that found in control striatum. The relation between these AChE chemical compartments and the distribution of preserved diaphorase neurons remained intact; NADPH-d neurons were predominantly observed in the matrix zone.

Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases

Because dopamine D2 receptors are known to be elevated in schizophrenic brain striata, this study examined whether a similar dopamine receptor elevation occurred in other diseases including neuroleptic-treated Alzheimers and Huntingtons diseases. The average D1 density in postmortem striata from Alzheimers patients was 17.6 +/- 0.1 pmol/g, similar to an age-matched control density of 16.6 +/- 0.4 pmol/g. The average D1 density in schizophrenia patients was 19.0 +/- 0.6 pmol/g, similar to the age-matched control density of 17.9 +/- 0.6 pmol/g. In Parkinsons disease patients, however, the D1 receptor density was elevated, with values of 22.8 +/- 1.2 pmol/g (in patients not receiving L-DOPA) and 19.6 +/- 1.5 pmol/g (in patients receiving L-DOPA) compared to the age-matched control density of 16.0 +/- 0.4 pmol/g. The D2 receptors in Alzheimers striata averaged 13.4 +/- 0.6 pmol/g (in patients who had not received neuroleptics), almost identical to the control density of 12.7 +/- 0.3 pmol/g. The average D2 density in neuroleptic-treated Alzheimers striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinsons disease patients, the D2 densities were elevated in tissues from patients not receiving L-DOPA (19.9 +/- 1.5 pmol/g in putamen and 14.8 +/- 1.2 pmol/g in striatum) compared to the age-matched control values of 13.0 +/- 0.4 pmol/g and 12.6 +/- 0.3 pmol/g, respectively. In Huntingtons disease patients, the D2 density averaged 7.5 +/- 0.4 pmol/g in patients who had not received neuroleptics, but was 10.3 +/- 0.6 pmol/g in those who had. Although all of the D1 and D2 densities in each of the above diseases and subgroups revealed a normal distribution pattern, the D2 densities in schizophrenia displayed a bimodal distribution pattern, with 48 striata having a mode at 14 pmol/g, and the other 44 striata having a mode at 26 pmol/g. Thus, compared to the neuroleptic-induced and unimodal elevations in D2 of 31% in Alzheimers disease and 37% in Huntingtons disease, the schizophrenic striata with a mode of 26 pmol/g (105% above control) appear to contain more D2 receptors than can be accounted for by the neuroleptic administration alone.

Kynurenine Pathway Measurements in Huntington's Disease Striatum: Evidence for Reduced Formation of Kynurenic Acid

Abstract: Recent evidence suggests that there may be over‐activation of the N‐methyl‐D‐aspartate (NMDA) subtype of excitatory amino acid receptors in Huntingtons disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16‐sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5‐hydroxyindoleacetic acid, 5‐hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p < 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.

Neurotransmitter receptor alterations in Parkinson's disease.

Abstract Neurotransmitter receptor binding for GABA, serotonin, cholinergic muscarinic and dopamine receptors and choline acetyltransferase (ChAc) activity were measured in the frontal cortex, caudate nucleus, putamen and globus pallidus from postmortem brains of 10 Parkinsonian patients and 10 controls. No changes in any of these systems were observed in the frontal cortex. In the caudaye nucleus, only the apparent dopamine receptor binding was altered with a significant 30% decrease in the Parkinsonian brain. Both cholinergic muscarinic and serotonin receptor binding were significantly altered in the putamen, the former increasing and the latter decreasing with respect to controls. In addition, ChAc activity was decreased in the putamen. In the globus pallidus, only ChAc activity was significantly changed, decreasing about 60%, with no change in neurotransmitter receptor binding. The results suggest that a progressive loss of dopaminergic receptors in the caudate nucleus may contribute to the decreased response of Parkinsonian patients to L-dopa and dopamine agonist therapy.

Regional mitochondrial respiratory activity in Huntington's disease brain

This study investigated mitochondrial respiratory activity in Huntingtons disease (HD) brain. Mitochondrial membranes from caudate and cortex of HD and non‐HD autopsied brains were assayed for succinate oxidation, cytochrome oxidase activity, and cytochromes b, cc1, and aa3. There was a significant decrease in HD caudate mitochondrial respiration, cytochrome oxidase activity, and cytochrome aa3, whereas cytochromes b and cc1 were normal. These findings are consistent with the hypothesis that mitochondrial dysfunction may contribute to the localized hypometabolism and progressive atrophy of the HD caudate.

Kynurenine pathway abnormalities in Parkinson's disease

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinsons disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT and SN of both PD(-) and PD(+) groups, and the ratio of KYN to 3OHKY was significantly reduced in the PT of the PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.

Gilles de la Tourette's syndrome. A postmortem neuropathological and immunohistochemical study.

Immunocytochemical studies of the human forebrain have shown that enkephalin-like, dynorphin-like and substance-P-like immunoreactivity (respectively ELI, DLI, and SPI) normally present in unique pattern (now termed woolly fibers) in the globus pallidus and substantia nigra, in which their concentration is at its densest. Quantitative determinations moreover indicate that the levels of all 3 peptides are higher in the globus pallidus and substantia nigra than in any other region of the brain. We report here the distribution of immunoreactivity of these 3 peptides in the brain of a patient showing the typical clinical manifestations of Gilles de la Tourettes syndrome (TS); a disease for which no characteristic or consistent neuropathological features have been discerned. In the case described here neuropathological examination by means of the usual histopathological methods showed no abnormalities to which the patients illness could be ascribed. ELI- and SPLI-positive woolly fibers were densely stained and of normal distribution. DLI-staining was, however, considerably less dense throughout the brain than normal. The most striking finding was the total absence of DLI-positive woolly fibers in the dorsal part of the external segment of the globus pallidus; the ventral pallidum showed very faint staining. These observations, which indicate a decrease of dynorphin in striatal fibers projecting to the globus pallidus, are, to our knowledge, the first evidence of a distinct pathological change in the brain in TS.

Clinical and neuropathologic assessment of severity in Huntington's disease

Clinical records were evaluated for 163 Huntingtons disease patients in whom postmortem brain specimens had been graded for degree of neuropathologic involvement in the striatum. Juvenile/adolescent onset (4 to 19 years of age) was associated with very severe neuropathologic involvement produced by an apparent rapid degenerative process. Cases of early (20 to 34 years) and midlife (35 to 49 years) onset had respectively less severe striatal involvement, suggesting a slower degenerative progression. High correlations among the grade of neuropathologic involvement, cell counts of neurons, and a rating of physical disability suggest that each represents a common underlying degenerative process of the disease. The relationship between the age at onset and the extent of neuropathologic involvement suggests that a single mechanism may determine both onset and rate of degenerative disease progression.

Morphometric analysis of the prefrontal cortex in Huntington's disease

We performed a morphometric analysis of cresyl violet-stained sections from the dorsolateral prefrontal cortex of 81 patients with Huntingtons disease (HD) (grades 2, 3, and 4) and 23 age-matched normal controls. We counted large pyramidal neurons, small neurons, astrocytes, oligodendroglia, and microglia under the guidance of a specifically predefined set of morphologic criteria for each cell type and recorded the thickness of each cortical layer. Our results demonstrate a selective and progressive loss of a subset of the large pyramidal neurons in cortical layers III, V, and VI of HD patients, and a decrease in the thickness of the respective cortical laminae. A genetically determined, cell-autonomous degeneration of cortical neurons could constitute the primary pathologic process. However, the loss of only a fraction of pyramidal cells suggests a parallel, or an alternative, possibility of a retrograde degeneration of cortical neurons that project solely, or principally, to the site of primary degeneration in caudate nuclei.