Solvent-associated olfactory dysfunction: not a predictor of deficits in learning and memory.

OBJECTIVE: The aim of the study was to evaluate associations between olfactory dysfunction and aberrations in learning and memory after chronic occupational exposure to mixed hydrocarbon solvents. METHOD: This was a cross-sectional, epidemiologic study of 187 paint manufacturing workers. The authors administered quantitative tests of olfactory function (the University of Pennsylvania Smell Identification Test) and neurobehavioral function (eight computer- and examiner-administered tests of learning and memory) to workers for whom detailed information was available on lifetime occupational exposure to solvents. RESULTS: Olfactory function test scores were positively correlated with performance on seven of eight of the tests of learning and memory in bivariate analyses. After adjustment for important confounding variables (i.e., age, vocabulary score, and cumulative exposure to hydrocarbon solvents) with multiple linear regression, olfactory function scores predicted performance only on the Wechsler Memory Scale Delayed Logical Memory test. CONCLUSIONS: Overall, the data did not reveal that olfactory dysfunction was correlated with decrements in various memory functions.

Memory complaints in older adults. Fact or fiction?

Complaints of poor memory by patients may be an early symptom of a pathologic process like Alzheimer's disease. It is therefore important to determine if patients' complaints of memory impairments are an accurate reflection of real memory disturbance. The relationship between memory complaints (metamemory) and objective memory performance, mood, age, verbal intelligence, and sex was examined in a group of 199 healthy, community dwelling adults (39 to 89 years old). Memory complaints demonstrated a stronger association with depressed mood than with performance on memory tests. Increasing reports of depressive symptoms were associated with more overall memory complaints. Verbal intelligence, age, and sex also contributed to memory complaints. Patients with higher verbal intelligence reported fewer complaints and placed less emphasis on forgetting. Older individuals reported greater frequency of forgetting and greater frequency of using memory techniques. Specific types of memory complaints, seriousness of forgetting, and types of memory aids employed are also described. These results showed that self-rating of memory disturbance by older adults may be related more to depressed mood than to poor performance on memory tests.

Neurocognitive effects of aluminum.

The neurocognitive effects of aluminum (Al) were studied in 35 hemodialysis patients. Higher Al levels were associated with a decline in visual memory. As Al levels increased, patients with lower vocabulary scores (a measure of premorbid intelligence) showed a decline in attention/concentration, frontal lobe functions, and on several neurocognitive measures, while those with higher vocabulary scores revealed no Al-related decline. These results suggest that individuals with lower verbal intelligence may possess less well-developed compensatory strategies to overcome the neurocognitive effects associated with Al. These data also indicate that Al is neurotoxic and, therefore, potential sources of environmental Al should be identified and eliminated.

Differential effects of cocaine and cocaine alcohol on neurocognitive performance.

OBJECTIVE: To investigate the dose-related effects of cocaine with or without alcohol use on the CNS by measuring performance on neurobehavioral tests. BACKGROUND: Chronic use of cocaine is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Specific neurobehavioral deficits in areas such as executive function and impulsivity would make it difficult for the cocaine abuser to discontinue using drugs. Because alcohol is often used in conjunction with cocaine, the CNS effects of alcohol when taken with cocaine deserve further investigation. METHOD: The authors evaluated the dose-related effects of cocaine and alcohol use on performance in a variety of neuropsychological tests after 1 to 3 days of abstinence and again after 4 weeks of abstinence. Fifty-six chronic cocaine abusers who had used cocaine during the past 24 to 48 hours volunteered to perform a battery of neuropsychological tests on two separate occasions during a period of enforced abstinence. In addition to using cocaine, most of the volunteers consumed alcohol. Approximately half of the participants consumed more than 10 alcohol-containing drinks per week. RESULTS: After controlling for the effects of age, sex, and intelligence on performance, the authors found dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1 to 3 days of abstinence, with these effects persisting after 4 weeks of abstinence. CONCLUSION: The concomitant use of cocaine and alcohol may have additive negative effects on the brain as compared to the use of only one of these two substances.

Dihydropteridine reductase activity: lack of association with serum aluminum levels and cognitive functioning in patients with end-stage renal disease.

Although increased levels of aluminum (Al) are present in patients with dialysis encephalopathy (DE), it is unclear if the association is causal. The enzyme dihydropteridine reductase (DHPR) plays a critical role in neurotransmitter formation and its activity. Elevated levels of Al are reported to decrease DHPR activity, which would alter neurotransmitter metabolism, thus producing DE. We examined the association between erythrocyte DHPR activity and Al levels, attention/psychomotor skills, and depression in a group of 21 patients with end-stage renal disease. DHPR activity was not related to Al level, mental status, psychomotor ability, or depression score. After administration of deferoxamine (an Al chelating agent), Al level increased significantly but DHPR activity remained the same. Our results suggest that the mechanism for the development for DE does not involve alterations of neurotransmitter metabolism caused by Al-mediated reductions in DHPR activity.

Memory impairment in abstinent MDMA ("Ecstasy") users.

BACKGROUND: Methylenedioxymethamphetamine (MDMA, or "Ecstasy") is a popular recreational drug of abuse that is known to damage brain serotonergic neurons in animals and possibly humans. Few functional consequences of MDMA-induced serotonin (5-HT) neurotoxicity have been identified, either in animals or humans. This study sought to determine whether individuals with a history of extensive MDMA use showed evidence of memory impairment, because brain serotonin has been implicated in mnemonic function. METHOD: The authors compared 24 abstinent MDMA users and 24 control subjects on several standardized tests of memory, after matching subjects for age, gender, educational level, and vocabulary score (a surrogate of verbal intelligence). The authors also explored correlations between changes in memory function and decrements in CSF 5-hydroxyindoleacetic acid (5-HIAA), which serves as a marker of central 5-HT neural function. RESULTS: Greater use of MDMA (total milligrams per month) was associated with greater impairment in immediate verbal memory (p < 0.02) and delayed visual memory (p < 0.06). Furthermore, lower vocabulary scores were associated with stronger dose-related effects, with men having greater dose-related deficits than women. Lastly, lower concentrations of CSF 5-HIAA were associated with poorer memory performance. CONCLUSION: Abstinent MDMA users have impairment in verbal and visual memory. The extent of memory impairment correlates with the degree of MDMA exposure and the reduction in brain 5-HT, as indexed by CSF 5-HIAA.

Neurologic health outcomes and Agent Orange: Institute of Medicine report.

The National Academy of Sciences' Institute of Medicine conducted an independent scientific investigation to evaluate the strength of evidence for human health effects among veterans exposed to herbicides used in Vietnam and to suggest future research recommendations. Neurologic domains where multiple studies had been performed in military, occupational, or environmental situations were (1) cognitive and neuropsychiatric effects, (2) motor/coordination dysfunction and other central nervous system disorders, and (3) peripheral neuropathy. In all categories, no strong evidence established an association between herbicides used in Vietnam and clinical neurologic disorders. Methodologic weaknesses, long durations between exposure and assessments, and poor exposure measures limited many studies. The committee concluded that the available evidence was insufficient to determine an association between neurologic disorders and exposure to herbicides used in Vietnam. Neurotoxicologic studies available did not suggest strong biological plausibility for neurologic alterations related to herbicide exposure. Furthermore, given the large uncertainties in the epidemiologic studies reviewed and inadequate control for important confounders, the committee could not quantify a degree of risk for neurologic disorders from herbicide exposure likely to be experienced by Vietnam veterans. Although not part of the neurologic report, the risk of brain tumors was considered in the cancer analysis, and the committee concluded that there is limited/suggestive evidence of no association between exposure to herbicides and brain tumors.

Neurobehavioral function and tibial and chelatable lead levels in 543 former organolead workers.

OBJECTIVE: To evaluate the associations between tibial lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and neurobehavioral function in former organolead manufacturing workers with past exposure to organic and inorganic lead. METHODS: Data were collected from 543 subjects with a mean age of 58 years and an average of 17.8 years since last lead exposure. Years since last exposure to lead was used to estimate tibial lead levels in the year of last occupational lead exposure, termed "peak tibial lead." Current tibial lead levels, measured by x-ray fluorescence, were extrapolated back using a clearance half-time of lead in tibia of 27 years, assuming first-order clearance from tibia. RESULTS: Peak tibial lead levels ranged from -2.2 to 105.9 microg Pb/g bone mineral, and DMSA-chelatable lead levels were between 1.2 and 136 microg. After adjustment for confounding variables, peak tibial lead was a significant negative predictor of performance on the Wechsler Adult Intelligence Scale-Revised vocabulary subtest (p = 0.02), serial digit learning test (p = 0.04), Rey Auditory-Verbal Learning Test (immediate recall and recognition, p = 0.03 for each), Trail Making Test B (p = 0.03), finger tapping (dominant hand [p = 0.02] and nondominant hand [p < 0.01]), Purdue pegboard (dominant hand, nondominant hand, both hands, and assembly, p < 0.01 for each), and Stroop Test (p < 0.01). Moreover, with one exception, average neurobehavioral test scores were poorer at higher peak tibial lead levels. DMSA-chelatable lead was only significantly associated with choice reaction time (p = 0.01). CONCLUSION: Peak tibial lead was consistently associated with poorer neurobehavioral test scores, particularly in the domains of manual dexterity, executive ability, verbal intelligence, and verbal memory.

Dose-related neurocognitive effects of marijuana use.

BACKGROUND: Although about 7 million people in the US population use marijuana at least weekly, there is a paucity of scientific data on persistent neurocognitive effects of marijuana use. OBJECTIVE: To determine if neurocognitive deficits persist in 28-day abstinent heavy marijuana users and if these deficits are dose-related to the number of marijuana joints smoked per week. METHODS: A battery of neurocognitive tests was given to 28-day abstinent heavy marijuana abusers. RESULTS: As joints smoked per week increased, performance decreased on tests measuring memory, executive functioning, psychomotor speed, and manual dexterity. When dividing the group into light, middle, and heavy user groups, the heavy group performed significantly below the light group on 5 of 35 measures and the size of the effect ranged from 3.00 to 4.20 SD units. Duration of use had little effect on neurocognitive performance. CONCLUSIONS: Very heavy use of marijuana is associated with persistent decrements in neurocognitive performance even after 28 days of abstinence. It is unclear if these decrements will resolve with continued abstinence or become progressively worse with continued heavy marijuana use.

Past adult lead exposure is associated with longitudinal decline in cognitive function.

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Neuropsychological assessment for detecting adverse effects of volatile organic compounds on the central nervous system.

Because there are no direct biological markers for the substances implicated in indoor air exposure, it is impossible to directly measure if an individual or group of individuals has been exposed to a potentially neurotoxic substance in the workplace. Behavioral changes may be the earliest and only manifestation of central nervous system (CNS) effects and are often too subtle to be revealed by routine physical or neurological examination. Neuropsychological techniques are sensitive to subtle behavioral/cognitive changes that can result from exposure to neurotoxins. These techniques consist of oral and written tests that are administered by a trained examiner on a one-to-one basis. In general, a wide variety of cognitive domains are evaluated. The typical battery generally includes assessing orientation, attention, intelligence, language, visual memory, verbal memory, perception, visuoconstruction, simple motor speed, psychomotor speed, and mood. As with most assessment techniques, the neuropsychological methods have limitations. One major drawback is the availability of appropriate norms that are used to compare the results of a specific individual. Because these tasks are greatly affected by age, intelligence, and in some instances sex, the availability of appropriate norms is mandatory to determine if the CNS has been effected. Although neuropsychological tests are sensitive to the presence of CNS involvement, they are not specific. Patterns of performance seen with specific instances of neurotoxic exposure may also be seen with a number of other diseases of the CNS such as dementia, cerebrovascular disease, hydrocephalus, or normal aging. In addition, neuropsychiatric symptoms such as anxiety and/or depression are often manifested as cognitive difficulties that will mimic the cognitive dysfunction seen with toxicity of the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)

The immune-enhancing effect of perioperative thymopentin administration in elderly patients undergoing major surgery.

The effects of perioperative administration of thymopentin (TP-5) on in vivo and in vitro measurements of cell-mediated immunity in elderly patients undergoing major surgery were investigated. A placebo-controlled study was conducted in 25 patients (mean age, 67 years) with congenital or acquired heart disease undergoing surgery with cardiopulmonary bypass. Patients were divided into three groups: Group 1 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively. Group 2 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively and 48 hours postoperatively. Group 3 patients were given placebo at corresponding times. Cell-mediated immunity measurements were the in vivo delayed-type hypersensitivity (DTH) response on day 0 and on day 7 to an antigen skin test battery. The in vitro studies included antigen cocktail-induced lymphocyte proliferation of peripheral blood mononuclear cells. The DTH response on day 7 after surgery was significantly suppressed in group 3 patients compared with the preoperative baseline value, while it remained unaltered in group 1 and 2 patients. There was a considerable difference of DTH measurements (number of positive antigen responses and sum of their mean diameters) between group 2 and 3 patients. Antigen cocktail-induced lymphocyte proliferation, following initial suppression in the majority of patients, was significantly different between the placebo group and patients in group 2 on day 7 after surgery. The data indicate that perioperative administration of TP-5 might be of considerable clinical utility in preventing a defective cellular immune response.

Clinical evaluation of 58 organolead manufacturing workers.

Fifty-eight workers were evaluated at a university-based occupational health clinic for potential health effects related to organic and inorganic lead exposures. The clinical evaluation included a history, physical, and laboratory examination, and in a subset of workers, neurobehavioral tests and nerve conduction studies. Workers reported symptoms that predominantly involved the central and peripheral nervous systems. Findings for which no alternative medical explanations could be found included neurobehavioral abnormalities (18 of 39 workers) and sensorimotor polyneuropathies (11 of 31 workers). The clinical presentation and evaluation of workers exposed to organic lead are discussed.

Clinical course of neuropsychological functioning after chronic exposure to organic and inorganic lead.

This case series describes the clinical course (12- to 28-month follow-up) of neuropsychological functioning in 23 workers who had chronic occupational exposure to a mixture of organic and inorganic lead. Significant improvement in performance was seen in 123 tests and deterioration in 323 tests. However, there was no significant change in the majority of tests (1923). Tests that showed deterioration were all tests of psychomotor/motor speed. In addition, 10 of 13 workers who completed a symptom checklist twice reported more frequent physical, cognitive, and affective symptoms at follow-up. This increase in symptoms was associated with psychomotor/motor slowing as compared to initial test performance. Many workers subjectively reported an increased frequency of memory and concentration problems at follow-up, although this change could not be documented objectively. Individual worker demographic and exposure characteristics were not predictive of changes in neuropsychological performance at retest. We propose a psychosocial mechanism to explain the increase in symptom severity and the psychomotor/motor slowing because environmental levels of lead declined during the inter-test interval.

Influence of thymopentin on postsurgical immune deficiency: a clinical pilot study.

The effect of a single dose (50 mg) of thymopentin, administered subcutaneously, on antigen-induced proliferation of peripheral blood mononuclear cells (PBMCs) was investigated in 25 volunteers (all over 50 years of age) and in nine patients undergoing major surgery. Blood samples from another nine patients having the same type of surgery were used as control in the second trial. A statistically significant increase in the proliferative response was observed in the group of volunteers two hours after thymopentin administration. This increment was not demonstrable as significant 24 h later. In contrast to this observation, the surgical procedure-induced significant decrement in the proliferation of PBMCs observed on the first and third postoperative days did not occur in the thymopentin-treated patients on the first postoperative day. This preventive effect of the single dose of thymopentin administered two hours before surgery was no longer demonstrable on the third postoperative day. Further studies are ongoing in order to establish a treatment regimen with thymopentin for the therapy of trauma-induced immune deficiencies.

First observations on high-dosed and long-term thymopentin treatment in active rheumatoid arthritis.

In this pilot study carried out in two centres, six male and two female patients with severe active rheumatoid arthritis (RA) (average duration over 10 years) were treated with thymopentin 50 mg in the form of prolonged i.v. injection (over 10 min), 3 times weekly for 3 to 20 weeks. Two of these patients were subsequently treated with different s.c. doses of thymopentin in a crossover fashion for more than two years, including periods without any treatment or treatment with placebo. The overall clinical efficacy was judged by assessing pain patterns and joint status and the functional stage of the patients according to Steinbrocker; in addition, the sedimentation rate was measured before and after the therapy. Seven out of eight patients showed definite improvement in their clinical status as assessed by the Steinbrocker scale. Most of the symptoms, particularly pain, capsular swelling, tenderness and morning stiffness, were remarkably reduced within 3 weeks of thymopentin treatment. Sedimentation rate decreased in five out of eight patients. Prolonged i.v. injections seemed to have somewhat better effects than s.c. administration; in the latter group the highest dose (3 X 100 mg/week or higher) produced the best results. During placebo treatment and during the medication-free intervals both groups of patients got worse. No side-effects occurred during the study.

Immunomodulation with thymopentin in humans.

The effect of thymopentin administered i.v. or s.c. on the levels of circulating specific IgM and IgG KLH (key-hole limpet haemocyanine) antibodies and non-specific immunoglobulins were measured at weekly intervals in elderly volunteers for three subsequent weeks after vaccination with 500 micrograms KLH. As compared with the placebo group, specific IgM and IgG antibody responses significantly increased in the s.c. treated group, but remained at significantly lower levels in the i.v. treated groups. Increases in non-specific immunoglobulin levels were observed after vaccination in the placebo group; no such increases appeared in the groups treated with thymopentin. The results demonstrate the immunomodulatory effect of thymopentin in humans. It is assumed that, depending on the route of application (which indirectly represents different doses), thymopentin can either stimulate or inhibit immune processes. As an immunomodulator it may represent a new therapeutic tool for immunostimulation as well as for specific immunosuppression.

Preliminary results on clinical and immunological effects of thymopentin in AIDS.

In an open study, 10 African patients with AIDS were treated with thymopentin 50 mg i.v. 3 times a week for 2 consecutive months: 1 month by i.v. direct injections and 1 month by 30-min i.v. infusions. In group A there were 6 patients with AIDS-lymphadenopathy characterized by weight loss, chronic fever, generalized lymphadenopathy and OKT-4 to OKT-8 ratio below 0.2. Group B consisted of 4 patients with AIDS and opportunistic infections. Immunological studies performed before, during and after therapy included lymphocyte count, T-cell subsets assessment, study of blastogenic response of lymphocytes to PHA and delayed hypersensitivity skin testing to 5 antigens. In group A, results after thymopentin i.v. direct injections showed a significant increase in OKT-3 and OKT-8 cells. After thymopentin i.v. infusion, blastogenic response to PHA increased significantly as compared with pretherapy values and to the values after i.v. direct injections. At the end of infusion therapy, skin tests became positive for 3 antigens (range 2-4). Furthermore, all 6 patients noted subjective improvement associated with significant weight gain and disappearance of fever. In contrast, in group B the clinical and immunological status worsened during therapy and two patients died from opportunistic infections. This preliminary study suggests that i.v. infusion with thymopentin may be useful in the early phase of the acquired immune deficiency syndrome as it produces symptomatic and immunological improvement.

The effect of thymopentin treatment on the relapse rate in frequently relapsing herpes simplex virus infections.

Twenty-four patients suffering from longstanding severe recurrent herpes simplex, who had not responded to prior therapy, were treated with s.c. thymopentin injections 50 mg, three times weekly, over a period of six weeks. They were followed up at weekly intervals over this period and then six weeks later. Moreover, the longest relapse-free period observed in the year after the treatment was recorded in the investigator's documentation. Thirteen of the 14 patients with labial herpes simplex and 10 of the 13 patients with genital herpes simplex improved markedly as shown by a decrease in the relapse rate of at least 50%, shorter episodes of relapse and improvement of symptoms such as pain and itching. Fourteen of these 27 patients experienced no relapse for a period longer than four months after cessation of the therapy. No serious side-effects were observed. Laboratory examinations before, during and after thymopentin did not reveal significant alterations except for an increase in the T-helper/T-suppressor ratio. The effect of thymopentin is assumed to be due to T-helper cell activation resulting in enhanced interleukin-2 production with subsequent proliferation of cytotoxic T lymphocytes and natural killer cells which are capable of producing immune interferon.

Interim results on the clinical effects of i.v. administered thymopentin in active rheumatoid arthritis.

Forty-one patients with active rheumatoid arthritis entered a controlled, double-blind, randomized study; 21 received prolonged i.v. injections (10 min) of thymopentin 50 mg 3 times a week for 3 consecutive weeks; the other 20 received placebo under the same conditions. The groups were comparable at the start of the study. Statistical tests of changes within the treatment groups after 3 weeks showed that the improvement achieved in the thymopentin group was significant (p less than 0.05 or p less than 0.01) for each clinical parameter, except for left-hand grip strength. On the other hand, no significant improvement was observed for any parameter except morning stiffness in the patients on placebo. The intergroup comparison showed significant differences, favouring thymopentin over placebo treatment, in the Ritchie index, scores for swollen joints, assessment of severity of pain and scores for changes in the activity of the disease. Only minor side-effects were experienced in the two treatment groups. The present placebo-controlled double-blind study confirms the previous positive results achieved in open studies, i.e., the beneficial therapeutic effect of prolonged i.v. injections of thymopentin in patients with severe rheumatoid arthritis observed after 3 weeks of therapy. The drug appears to be safe at the dose regimen used.