Analysis of TAF90 mutants displaying allele-specific and broad defects in transcription.

Yeast TAF90p is a component of at least two transcription regulatory complexes, the general transcription factor TFIID and the Spt-Ada-Gcn5 histone acetyltransferase complex (SAGA). Broad transcription defects have been observed in mutants of other TAF(II)s shared by TFIID and SAGA but not in the only two TAF90 mutants isolated to date. Given that the numbers of mutants analyzed thus far are small, we isolated and characterized 11 temperature-sensitive mutants of TAF90 and analyzed their effects on transcription and integrity of the TFIID and SAGA complexes. We found that the mutants displayed a variety of allele-specific defects in their ability to support transcription and maintain the structure of the TFIID and SAGA complexes. Sequencing of the alleles revealed that all have mutations corresponding to the C terminus of the protein, with most clustering within the conserved WD40 repeats; thus, the C terminus of TAF90p is required for its incorporation into TFIID and function in SAGA. Significantly, inactivation of one allele, taf90-20, caused the dramatic reduction in the levels of total mRNA and most specific transcripts analyzed. Analysis of the structure and/or activity of both TAF90p-containing complexes revealed that this allele is the most disruptive of all. Our analysis defines the requirement for the WD40 repeats in preserving TFIID and SAGA function, demonstrates that the defects associated with distinct mutations in TAF90 vary considerably, and indicates that TAF90 can be classified as a gene required for the transcription of a large number of genes.

Alpha-melanocyte-stimulating hormonelike immunoreactivity is increased in cerebrospinal fluid of patients with Parkinson's disease.

We measured alpha-melanocyte-stimulating hormonelike immunoreactivity in cerebrospinal fluid of 12 healthy control subjects and nine patients with Parkinson's disease, four of whom had never been treated. Mean cerebrospinal fluid alpha-melanocyte-stimulating hormonelike immunoreactivity concentration was two-fold greater in parkinsonian patients (44.1 +/- 9.3 [SD] pg/mL) as compared with control subjects (21.8 +/- 10.0 pg/mL). No significant correlation was found between cerebrospinal fluid alpha-melanocyte-stimulating hormonelike immunoreactivity concentrations and patient age, disease severity, or duration of disease. These results suggest a functional relation between dopaminergic and melanotropinergic systems in the human brain.

Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts.

BACKGROUND: Since 1985, treatment of idiopathic Parkinson's disease (PD) by surgical transfer of adult or fetal chromaffin tissue or of fetal central neural tissue to the brains of afflicted patients has been attempted, with variable clinical results. Neuropathologic studies of the status of these transplants are few and show wide variation in degree of graft survival. METHODS: We report the case of a 52-year-old man, who, 23 months earlier, received both intrastriatal implantation and intraventricular infusion of tissues derived from fetuses of 15 to 16 weeks and 5 to 6 weeks gestational age. Clinical improvement, as measured by increased amounts of "on" time with reduced levodopa requirements, seemed to occur over the subsequent months. He died suddenly at home after a several-hours interval of progressive lethargy and breathing difficulties. RESULTS: At autopsy, the diagnosis of PD was confirmed. Intrastriatal graft sites were identified, but contained no viable neurons; astrogliosis, focal microgliosis, and mixed inflammatory response, suggesting allograft rejection, were present. Surprisingly, the intraventricular tissues survived and showed ectodermal and mesenchymal, but no neural, differentiation, as well as cellular response; the left lateral and fourth ventricles were filled completely by this proliferated tissue. CONCLUSIONS: By intraventricular infusion, tissues from early-gestation sources can engraft successfully, grow, and survive for at least 23 months in the brain of a PD patient. However, contamination by, or differentiation into, nonneural tissues can occur, can lead to proliferation of tissues within ventricular spaces, and may result in ventricular obstruction. Grafts, whether intraventricular or intraparenchymal, are capable of inciting host responses, which in turn may limit their long-term survival. Finally, post-transplant clinical improvement in symptoms of PD may be unrelated to survival of engrafted neurons.

Plasma growth hormone and prolactin response to dopaminergic GABAmimetic and cholinergic stimulation in Huntington's disease.

We studied the acute effects of pharmacologic stimulation of neurotransmitter systems implicated in growth hormone and prolactin regulation in eight patients with Huntington's disease and matched control subjects. Both apomorphine, a dopamine agonist, and muscimol, a GABA agonist, produced an exaggerated rise in plasma growth hormone levels in the Huntington patients. Neither the growth hormone response to a muscarinic agonist, arecoline, nor the prolactin response to any of these drugs differed in the patients and controls. Loss of somatostatin activity in the hypothalamic-pituitary axis in Huntington's disease could account for these endocrinologic changes.

Long-term efficacy of bromocriptine in Parkinson disease.

Twenty-eight patients with Parkinson disease (PD) were treated with bromocriptine for at least 2 years (mean, 2.8 years; range, 2 to 5 years). All of them had first been treated with levodopa (alone or combined with carbidopa, as Sinemet) for 7.4 years (range, 1 to 10 years). At the time bromocriptine was started, all were showing increasing disability. In these patients, attempts to increase levodopa resulted in adverse effects, and attempts to decrease levodopa resulted in increased parkinsonism. Bromocriptine (mean daily dose, 56 mg) was added to levodopa and resulted in improvement of at least one stage (Hoehn and Yahr scale) in 21 of the patients. After 2 years, five of these patients continue to maintain this improvement. The remaining patients, although there has been deterioration, maintain some of their original improvement. Bromocriptine, when added to levodopa, results in improvement that is maintained, in part, for at least 2 years. The ratio of bromocriptine to levodopa has to be periodically readjusted.

Lysine vasopressin in Alzheimer disease.

The effects of lysine vasopressin on memory and cognitive deficits in Alzheimer disease was investigated. In a double-blind study, seven patients were given 16 units of lysine vasopressin per day for 10 days and were compared with seven different patients receiving placebo. No significant difference in performance between the vasopressin and placebo-treated groups was found in tests designed to evaluate learning, memory, and perception. However, significantly greater improvement in reaction time was seen in the vasopressin-treated group, although this effect was delayed and may have been contributed to by factors other than drug activity.

Lisuride versus bromocriptine treatment in Parkinson disease: a double-blind study.

Twenty-eight parkinsonian patients were studied in a double-blind, crossover comparison of lisuride and bromocriptine. All but two patients completed the study, with each drug adjusted to an optimal dose (mean daily intake of 4.5 mg for lisuride and 56.5 mg for bromocriptine). Treatment with each drug was given for 7 to 10 weeks; three assessments were made at biweekly intervals with optimal dose levels. Conventional antiparkinsonian medications, including levodopa, were not changed. Efficacy and adverse effects were assessed by objective and subjective techniques. The only significant difference was slightly better control of akinesia with bromocriptine. There was considerable variability in the optimal dose of each drug, though the clinical profile of lisuride was quite similar to that of bromocriptine.

Variable absorption of carbidopa affects both peripheral and central levodopa metabolism.

Carbidopa (CD), a competitive inhibitor of aromatic l-amino acid decarboxylase that does not cross the blood-brain barrier, is routinely administered with levodopa (LD) to patients with Parkinson disease (PD) to reduce the peripheral decarboxylation of LD to dopamine. Using a stable isotope-labeled form of LD, the authors examined in 9 PD patients the effects of variable CD absorption on peripheral and central LD metabolism. Subjects were administered orally 50 mg of CD followed in 1 hour by a slow bolus intravenous infusion of 150 mg stable isotope-labeled LD (ring 1',2',3',4',5',6'-13C). Eight patients underwent a lumbar puncture 6 hours following the infusion. Blood and cerebrospinal fluid (CSF) samples were analyzed for labeled and unlabeled metabolites using a combination of high-performance liquid chromatography and mass spectrometry. When patients were divided into "slow" and "rapid" CD absorption groups, significantly greater peripheral LD decarboxylation (as measured by area under the curve [AUC]-labeled serum HVA) was noted in the poor absorbers (p = 0.05, Mann-Whitney U test). Elimination half-lives for serum LD did not differ between groups, suggesting a further capacity for decarboxylation inhibition in the "rapid" absorbers. A significant correlation between AUC serum CD and percent-labeled HVA in CSF was found for all patients (R = 0.786, p = 0.02). "Rapid" as compared to "slow" CD absorbers had significantly more percent-labeled CSF HVA (60 vs. 49, p = 0.02, Mann-Whitney U test), indicating greater central-labeled DA production in the better CD absorbers. The data suggest that peripheral aromatic l-amino acid decarboxylase activity is not saturated at CD doses used in current practice. The authors believe that future studies to better examine a dose dependence of CD on peripheral LD decarboxylation and LD brain uptake are warranted.

GM1 gangliosides alter acute MPTP-induced behavioral and neurochemical toxicity in mice.

We investigated the effect of GM1 gangliosides on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson disease. Five groups of mice (saline, GM1 (30 mg/kg), MPTP, MPTP + GM1 (15 mg/kg), MPTP + GM1 (30 mg/kg] were compared. GM1 was given daily via intraperitoneal injection before and during 13 daily doses of MPTP (30 mg/kg). Mice were tested for locomotion (1) within 2 h of an MPTP dose (to measure reduced motor activity), and (2) within 24 h of an MPTP dose (after animals had recovered and exhibited hyperactivity). We found that mice given GM1 gangliosides exhibited significantly less MPTP-induced behavior. This effect was most evident with the 15 mg/kg GM1 dose. GM1 also appeared to attenuate MPTP-induced neurochemical changes. GM1 effects indicating enhancement of DA turnover and preservation of DA, DOPAC and HVA concentrations in the striatum were found after the 8th MPTP dose. These latter neurochemical changes, however, were transient and not present after the 13th MPTP dose. Our data would suggest that gangliosides may reduce acute MPTP-induced neurotoxicity in mice either through an increase in DA neuron survival and/or the augmentation of striatal DA activity.

Reversible pathologic jealousy (Othello syndrome) associated with amantadine.

We describe a case of pathologic jealousy (Othello syndrome) in a patient with Parkinson disease, which abated after discontinuing amantadine. We indicate that early recognition and treatment of the syndrome in this disease may avert physical violence. We also believe that our report further suggests a link between this specific behavioral disorder and dopaminergic activity.

Magnitude of response to levodopa in Parkinson disease as it relates to peripheral and central measurements of levodopa and associated metabolites.

The relationships between magnitude of response to orally administered carbidopa/levodopa (CD/LD) and serum/cerebrospinal fluid (CSF) concentrations of levodopa (LD), 3-O-methyldopa (3-O-MD), and homovanillic acid (HVA) were studied in 15 patients with chronic LD-treated Parkinson disease. The degree of clinical benefit derived from a 25/250 tablet of CD/LD could not be correlated with absolute serum levels of LD, 3-O-MD or LD/3-O-MD ratios. CSF levels of LD and 3-O-MD were also not associated with improvement. CSF levels of HVA, however, did significantly correlate with magnitude of response to LD. Furthermore, CSF HVA levels were not dependent on previous LD dosage. Our data suggest that in chronic LD-treated patients, central factors related to the integrity of the nigrostriatal tract may be a more important determinant of magnitude of response to LD than peripheral elements affecting the amount of LD entering the central nervous system.

A comparison of NES2 and traditional neuropsychological tests in a neurologic patient sample.

The Neurobehavioral Evaluation System (NES), a computer-assisted battery of behavioral tests, has been widely used to detect central nervous system dysfunction in occupational and environmental settings and has recently been adapted for testing of neurological patients. The purpose of the present study was to assess the relationship between NES tasks and the traditional neuropsychological tests from which many of the NES tests were developed. For this purpose, comparisons were made between scores on NES tests and traditional neuropsychological tests designed to measure functioning in the same cognitive domains in a sample of patients with idiopathic Parkinson's disease (PD). As has been found in prior studies with normal subjects, correlations between traditional and NES2 tests varied from low to moderate. Correlations tended to be low when the modality of stimulus presentation or responses was different in the NES tests from the traditional tasks (e.g., verbal rather than visual) or when divergent and highly specific cognitive functions were being measured by the tests.

Treatment of Parkinson's disease with dopamine agonists: a review.

Bromocriptine and lergotrile were administered to 81 patients with Parkinson disease (PD) and increasing disability despite optimal treatment with levodopa (secondary levodopa failures). Sixty-six patients were treated with bromocriptine and 53 patients were treated with lergotrile. Both groups had significantly decreased rigidity, tremor, bradykinesia and gait disturbance upon addition of bromocriptine or lergotrile to levodopa. Twenty-five patients improved at least one-stage on bromocriptine, and 21 improved at least one-stage on lergotrile. The mean dose of bromocriptine was 47 mg, and the mean dose of lergotrile was 49 mg, permitting a 10% reduction in levodopa. Bromocriptine was discontinued in 29 of 66 patients because of adverse effects, including mental changes (14 patients) and involuntary movements (9 patients). Lergotrile was discontinued in 33 of 53 patients because of adverse effects including hepatotoxicity (11 patients) and mental changes (12 patients). The results of treatment with bromocriptine or lergotrile were comparable, with patients either responding or not. Bromocriptine will shortly be available for use in PD. Lergotrile, because of the hepatotoxicity, will not.

Speech monitoring skills in Alzheimer's disease, Parkinson's disease, and normal aging.

We examined the abilities of 15 patients with dementia of the Alzheimer type (DAT), 22 patients with Parkinson's Disease (PD), and 141 healthy subjects (ranging in age from 30 to 79 years) to detect and correct their own speech errors. Each subject was shown the Cookie Theft picture of the BDAE (Goodglass & Kaplan, 1972. The assessment of aphasia and related disorders. Philadelphia: Lea & Febiger.) and instructed to tell the examiner the "...story of what's happening in the picture." Self-monitoring performance was assessed by tabulating the number of uncorrected errors as well as repaired errors. We divided repairs into two types based on the psycholinguistics literature (van Wijk & Kempen, 1987. Cognitive Psychology, 19, 403-440). Speech corrections were judged to be lemma repairs when the reparandum was a single word, and reformulation repairs when a new syntactic constituent was added to the reparandum. Patients with DAT corrected only 24% of their total errors and patients with PD only 25%. Healthy subjects, by contrast, corrected from 72 to 92% of their total errors. Patients with DAT tended to rely on reformulation repairs while patients with PD used both repair types about equally often. While healthy elderly Ss (in the 70s group) utilized lemma repairs more often than the reformulation strategy, all other healthy Ss used both strategies about equally often. Across all groups naming performance correlated negatively with numbers of undetected errors. Results point to a previously unrecognized communication disorder associated with PD and DAT and manifested by an impairment in the ability to correct output errors. This impairment may be related to attentional and frontal dysfunction in the two patient groups.

Counterfactual cognitive deficit in persons with Parkinson's disease.

BACKGROUND: Counterfactuals are mental representations of alternatives to past events. Recent research has shown them to be important for other cognitive processes, such as planning, causal reasoning, problem solving, and decision making-all processes independently linked to the frontal lobes. OBJECTIVE: To test the hypothesis that counterfactual thinking is impaired in some patients with Parkinson's disease and is linked to frontal dysfunction in these patients. Methods. Measures of counterfactual processing and frontal lobe functioning were administered to 24 persons with Parkinson's disease and 15 age matched healthy controls. Results. Patients with Parkinson's disease spontaneously generated significantly fewer counterfactuals than controls despite showing no differences from controls on a semantic fluency test; they also performed at chance levels on a counterfactual inference test, while age matched controls performed above chance levels on this test. Performance on both the counterfactual generation and inference tests correlated significantly with performance on two tests traditionally linked to frontal lobe functioning (Stroop colour-word interference and Tower of London planning tasks) and one test of pragmatic social communication skills. CONCLUSIONS: Counterfactual thinking is impaired in Parkinson's disease. This impairment may be related to frontal lobe dysfunction.

The proteasome regulates the UV-induced activation of the AP-1-like transcription factor Gcn4.

The proteasome is well known for its regulation of the cell cycle and degradation of mis-folded proteins, yet many of its functions are still unknown. We show that RPN11, a gene encoding a subunit of the regulatory cap of the proteasome, is required for UV-stimulated activation of Gcn4p target genes, but is dispensable for their activation by the general control pathway. We provide evidence that RPN11 functions downstream of RAS2, and show that mutation of two additional proteasome subunits results in identical phenotypes. Our analysis defines a novel function of the proteasome: regulation of the RAS- and AP-1 transcription factor-dependent UV resistance pathway.

Age influences magnitude but not duration of response to levodopa.

Following an all-night fast, 45 patients with Parkinson's disease were examined using certain motor items present in the United Parkinson's Disease Rating Scale. All were given a single tablet of carbidopa 25 mg and levodopa 250 mg and re-examined 90 minutes later. In addition to this evaluation, 23 of these patients underwent further scoring over a 4-hour period. A significant negative correlation was found between age and one important aspect of drug-derived benefit: magnitude of response. In contrast, age had no apparent influence on duration of benefit from the drug. Although baseline (fasting) scores were predictably correlated with duration of disease, magnitude of response was not adversely influenced by this variable. Not all Parkinsonian signs were equally influenced by age. Whereas the poor response of gait and bradykinesia appeared to be dependent on age, no such effect was noted on rest tremor scores. The data indicate that in patients with Parkinson's disease treated long term, factors associated with age rather than duration of disease may have a stronger adverse influence on magnitude of response to levodopa.

Twenty-four hour plasma levels of growth hormone and prolactin in Huntington's disease.

Since hypothalamic neural degeneration is thought to occur in individuals with Huntington's disease, anterior pituitary hormone secretion which is in part regulated by the hypothalamus, was postulated to be altered in patients with this disease. To test this proposal, nine females with Huntington's disease were matched with controls to participate in a 24-hour basal level study of growth hormone and prolactin concentration in plasma. Patients who were free from all centrally active medication for at least six months and normal volunteers had blood sampled at 30-minute intervals over 24 hours in a minimal stress environment. The results demonstrated that plasma levels of growth hormone were elevated throughout the 24-hour time period in Huntington's disease individuals. Despite the elevation, the mean growth hormone curve of the Huntington's disease group retained characteristics similar to the control curve throughout the 24-hour time. Basal 24-hour plasma prolactin concentrations in Huntington's disease patients showed no difference from those in control individuals.

Grammaticality judgments and sentence comprehension in Parkinson's disease: a comparison with Broca's aphasia.

In order to test the hypothesis that significant linguistic deficits could be associated with predominantly subcortical dopaminergic pathways which projected to the frontal lobes (in patients with Parkinson's Disease-PD), we compared language performance in PD patients to that of Broca's aphasics with linguistic deficits. On tests of grammaticality judgements and sentence comprehension, performance by patients with Parkinson's Disease did not vary with different types of sentence structure (as was the case with the aphasics) and was instead, uniformly high (about 75% correct). Comprehension performance, however, did significantly decline in a subgroup of patients with PD who were tested when withdrawn from their dopaminergic medications. We conclude that patients with treated Parkinson's Disease evidence no selective linguistic dysfunction. When, however, they are withdrawn from dopaminergic medication language functions suffer.

Neuropsychological profile linked to low dopamine: in Alzheimer's disease, major depression, and Parkinson's disease.

A distinct pattern of neuropsychological deficits was associated with low homovanillic acid (HVA) in the cerebrospinal fluid of 21 patients with: Alzheimer's disease (9), Parkinson's disease (8) and major depressive disorders (4). Regardless of clinical diagnosis, patients with low HVA were slower on a test of efficiency of processing timed information, and showed greater benefit from semantic structure on a verbal fluency task than patients with high HVA. However, low HVA subjects were not significantly impaired on confrontation naming (Boston Naming Test). Across three diagnostic groups, patients with lower HVA also tended to have more extrapyramidal motor signs and were significantly more depressed. These results demonstrate a significant relationship between specific neuro-behavioural deficits and dopaminergic activity which cuts across traditional diagnostic categories.