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.

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.

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.

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)

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.

Simple visual reaction time in organolead manufacturing workers: influence of the interstimulus interval.

The authors conducted this investigation to study the effects of interstimulus interval duration for a given simple visual reaction time trial on the relationship between lead exposure and reaction time. Organolead manufacturing workers (n=222) and nonexposed referents (n=62) were administered a neurobehavioral test battery that included simple visual reaction time. Simple visual reaction time was measured over 44 trials; interstimulus intervals ranged from 1 to 10 s in a randomly generated sequence that was identical for all study subjects. Mean reaction times for both lead-exposed and nonexposed subjects were longest for interstimulus intervals of 1 and 2 s. Mean reaction times in response to moderate (4-6 s) and long (7-10 s) interstimulus intervals were mainly associated with lead exposure; this association led the authors to suggest that interstimulus interval duration modifies the relationship between lead exposure and simple visual reaction time performance. In simple visual reaction time protocols, stronger associations between reaction time and lead exposure may be found if the analysis trials are separated with interstimulus intervals of less than 3 s duration.

Environmental lead exposure and cognitive function in community-dwelling older adults.

OBJECTIVE: To determine if long-term exposure to high levels of lead in the environment is associated with decrements in cognitive ability in older Americans. METHODS: We completed a cross-sectional analysis using multiple linear regression to evaluate associations of recent (in blood) and cumulative (in tibia) lead dose with cognitive function in 991 sociodemographically diverse, community-dwelling adults, aged 50 to 70 years, randomly selected from 65 contiguous neighborhoods in Baltimore, MD. Tibia lead was measured with (109)Cd induced K-shell X-ray fluorescence. Seven summary measures of cognitive function were created based on standard tests in these domains: language, processing speed, eye-hand coordination, executive functioning, verbal memory and learning, visual memory, and visuoconstruction. RESULTS: The mean (SD) blood lead level was 3.5 (2.2) microg/dL and tibia lead level was 18.7 (11.2) microg/g. Higher tibia lead levels were consistently associated with worse cognitive function in all seven domains after adjusting for age, sex, APOE-epsilon4, and testing technician (six domains p

Neuropsychological evaluation for detecting alterations in the central nervous system after chemical exposure.

Individuals with multiple chemical sensitivity (MCS) report decreased attention/concentration, memory loss, disorientation, confusion, fatigue, depression, irritability, decreased libido, sleep disturbances, headaches, and weakness. These neurobehavioral symptoms represent possible alterations in the central nervous system (CNS). The evaluation of neurobehavioral functioning using neuropsychological techniques provides an indirect method for determining the integrity of the CNS. However, caution must be used in interpreting neuropsychological test results, since this technique is extremely sensitive but is not specific. Clinically significant aberrant test performance may be noted after chemical exposure as well as with other diseases of the CNS. In addition, neuropsychiatric conditions such as anxiety and depression are often manifested as cognitive difficulties that are similar in pattern to the cognitive dysfunction caused by toxic chemicals. Herein, limitations and cautions in the interpretations of neuropsychological test results are discussed.

Neurobehavioral performance in multiple chemical sensitivities.

Individuals with Multiple Chemical Sensitivities (MCS) frequently report difficulties in attention/concentration, memory and accuracy and speed of problem solving. We evaluated neurobehavioral functioning in 35 chemically exposed patients referred to our Occupational and Environmental Neurology Clinic. Of these 35 patients, 17 presented with symptoms of MCS and 16 patients reported no symptoms of MCS. In addition, we used a group of 126 healthy controls for comparison. The performance of the MCS group was not significantly different from that of the control group on tests of verbal learning and memory, executive functioning, and psychomotor functioning. The MCS group performed below the control group on a test of visual learning and memory, but this performance was similar to the group with chemical exposure and no MCS. Therefore, performance on objective neurobehavioral tests did not confirm the most frequently reported subjective complaints of patients with MCS. These results suggests that patients with symptoms of MCS do not have compromised central nervous system functioning.

Use of neuropsychological testing in idiopathic environmental testing.

Individuals with idiopathic environmental intolerance (IEI) report fatigue, headaches, weakness, malaise, decreased attention/concentration, memory loss, disorientation, confusion, and psychological disturbances. These neurobehavioral symptoms may be a sign of possible alterations in the central nervous system (CNS). The evaluation of neurobehavioral functioning using standardized testing provides a surrogate measure of integrity of the CNS. However, the interpretation of neuropsychological test results must be made cautiously since this technique is extremely sensitive, but not specific. Abnormal test results could be due to a neurological disorder, a medical disorder, or a neuropsychiatric disorder. Therefore, when evaluating patients who present with symptoms of IEI, abnormal neurobehavioral results should not be attributed routinely to environmental chemical exposure until other causes are systematically ruled out.

Chronic cocaine use as a neuropsychiatric syndrome: a model for debate.

In humans, chronic cocaine abuse is associated with changes in the central nervous system (CNS). Neuropathological changes include cerebrovascular events, EEG abnormalities, vasculitis, seizures, and decrements in neurobehavioral performance. The acute administration of cocaine is associated with acute psychotic episodes and paranoid states while withdrawal from the drug is often associated with depressed mood. The mechanistic basis of these behavioral states is not known. Given the structural and functional changes associated with cocaine use, we propose that the chronic heavy use of cocaine may result in a neuropsychiatric syndrome which might be associated with neuropsychological changes that are not obvious during routine clinical evaluation of drug-using individuals. This disconnection syndrome, because of its sublety, might have deleterious effects on both acute and long-term therapeutic interventions with these subjects. An approach which deals with cocaine abuse as a neuropsychiatric disorder might be more beneficial to the long-term goal of treating these patients. This approach entails a neurobehavioral evaluation which will be comprised of a thorough neurological and psychiatric examination, neuropsychological testing, and imaging studies. The results of this evaluation would provide a more rational basis for cognitive and/or pharmacological therapies.

Dose-related neurobehavioral effects of chronic cocaine use.

Although cocaine use is a significant public health problem, there is a paucity of scientific data on long-term neurobehavioral effects. This study examined the dose-related association between chronic cocaine use and neurobehavioral performance. A battery of neuropsychological tests was administered to 30 abstinent chronic cocaine abusers and 21 non-drug-using control subjects matched for age, education, and intelligence. After controlling for age, education, and intellectual ability, greater use of cocaine (grams per week) was associated with larger decrements on tests measuring executive functioning, visuoperception, psychomotor speed, and manual dexterity. These results suggest that chronic cocaine use is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Knowledge of specific cognitive processing deficits in chronic cocaine users would be useful for designing individually tailored drug treatment programs.

The neuropsychiatry of chronic cocaine abuse.

This review integrates findings from neuropsychological, PET, and MRI studies in human subjects and neurochemical findings in animals to make inferences about neuropsychiatric consequences of chronic abuse of cocaine. It also aims to develop insights into brain-behavioral relationships that may explain the perpetuation of addictive behaviors. Such insights promise to lead to a better understanding of the neuropsychiatry of cocaine abuse and to promote the development of more efficacious treatments. The authors present evidence suggesting that cocaine abusers have specific dysfunction of executive functions (decision making, judgment) and that this behavior is associated with dysfunction of specific prefrontal brain regions, the orbitofrontal cortex, and anterior cingulate gyrus. Suggestions for future research and treatment are also discussed.