Cognitive impairment and sensory loss associated with chronic low-level ethylene oxide exposure.

A 29-year-old college graduate worked for 10 years adjacent to an ethylene oxide (EtO) chemical sterilizer. When the sterilizer was closed, levels of EtO in the air around the sterilizer were 4.2 ppm (OSHA maximum level, 1 ppm). Seven years after beginning work with EtO, she experienced impaired memory, increased irritability, clumsiness, and falling. Three years later exposure ceased, and symptoms markedly improved over the next few months, but did not disappear entirely. Neurologic and neuropsychological exams 1 year after exposure ceased demonstrated emotional lability, impaired concentration, cognitive slowing, impaired recent and remote memory, and impaired thermal and vibratory sense in distal limbs. Her pattern of relatively preserved learning and profound forgetting distinguished her from most other subjects with memory disorders. No other causes for the condition were identified.

Progressive dementia, visual deficits, amyotrophy, and microinfarcts.

Data from three patients and 22 previously reported cases suggest that cerebral microinfarction causes a recognizable clinical syndrome. All cases present with stroke, followed by progressive dementia and often with visual field deficits, peripheral vascular disease, and signs of motor neuron dysfunction. The average age at onset is 45, and most patients have been men. Many patients have had valvular or ischemic heart disease; in one of our cases, mitral stenosis caused embolic microinfarcts.

Chronic oral physostigmine without lecithin improves memory in Alzheimer's disease.

Sixteen patients with early Alzheimer's disease (AD) completed a 3-month outpatient double-blind parallel trial of oral physostigmine versus placebo. Ten subjects received drug; six received placebo. After a dose-titration phase, each patient was placed on his or her best dose of drug or placebo. Subjects were evaluated with both memory and nonmemory tasks. Seven of the ten drug-treated patients, but none of the six placebo-treated patients, demonstrated improvement on a selective reminding task, a test of verbal memory. Family members reported improvement in six of ten drug-treated patients and none of six placebo-treated individuals. There was a trend toward greater improvement with increasing drug dose. There was no improvement on the nonmemory tests administered. The data indicate that oral physostigmine improves memory but not other areas of cognition.

Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease.

Alzheimer patients were treated with lecithin and gradually increasing doses of oral physostigmine during a drug trial to determine if these compounds would improve memory. Memory was measured using a selective reminding task. Of 16 patients, 10 showed improvement in total recall, retrieval from long-term storage and a decrease in intrusions. The optimal dose was 2.0 mg or 2.5 mg of physostigmine per dose for most patients. During a replication study, all 10 patients again responded. During long-term (4 to 20 months) treatment of five patients, most demonstrated continued drug response initially but then lost responsiveness to physostigmine and their dementia progressed. Physostigmine treatment appeared to improve memory with or without concomitant lecithin therapy. However, progressive dementia ensued despite physostigmine therapy. The degree of memory improvement correlated with increasing cerebrospinal fluid cholinesterase inhibition suggesting that memory improvement is associated with entry of physostigmine into the brain.

Guaranteed stimulus-processing in the evaluation of memory and learning.

A test of memory and learning with guaranteed initial stimulus-processing was validated and is here presented with norms for 70-79 year old and 80-89 year old community residents vs. nursing-home residents. The test procedure also allows incidental observation of stereognosis, object-naming, and left-right orientation, screens for depression, and elicits rapid retrieval of words from semantic categories--all common aspects of evaluation for dementia. A validation study showed a significant difference between 21 moderately impaired and 21 unimpaired elderly nursing home residents grouped by their scores on Blessed, Tomlinson and Roth's (1968) "mental test". Reliability was determined by coefficient alpha, which yielded an estimated correlation of .84 between recall (retrieval) scores and errorless true scores. Storage scores were correlated .72 with retention after three weeks (p. less than .01), and storage and retrieval were not significantly correlated with each other when mental status was partialed out. Storage impairment appeared more significant in dementia than retrieval impairment, which occurred in normal aging as well. Norms for community-active vs. nursing-home-residing 70 and 80 year olds are provided which allow the separate evaluation of total recall, storage, retrieval, and response to reminders.

Cross-cultural and multi-ethnic dementia evaluation by mental status and memory testing.

Two studies investigated aspects of cross-cultural dementia evaluation. The first explored consequences of using different mental status tests; the second compared mental status and memory assessments for normal individuals aged 70-79 and 80-89 in Japan and in America. In a dementia screening clinic, scores from the Hasegawa mental status test could be converted to the Blessed scale without influencing patient classification (impaired vs. unimpaired). Younger subjects were slightly superior to older subjects in mental status in both comparison groups. Both Japanese groups performed better on the memory test than even the younger American group.

Test profile of cholinergic dysfunction and of Alzheimer-type dementia.

A characteristic profile of subtest scores from the Wechsler Adult Intelligence Scale (WAIS) similar to that seen in clinically tested dementia patients was found in 10 of 19 normal young adult subjects with a drug-induced cholinergic deficiency of mental functioning but in only 4 of 22 control subjects. The same subtest profile was then found in test data from two groups of consecutive dementia patients (61 and 77 patients, respectively) with research diagnoses of Alzheimer-type dementia (DAT, senile and presenile), multi-infarct, and other dementias. The profile identified 44% of testable patients with AD and was 96% specific to DAT (only two false positives). A Verbal-Performance IQ discrepancy of 15 or more points was associated with cholinergic dysfunction in the normal drug subjects, but this IQ-score discrepancy did not differentiate AD from multi-infarct dementia patients. It was concluded that the subtest profile could contribute to the differentiation of DAT from other dementias. The association of this profile with drug-induced cholinergic deficiency suggested that the cholinergic deficiency of DAT might be responsible for the intellectual changes seen in this disease.

Recovery of intellectual ability after closed head-injury.

Seven children with intellectual and personality changes after closed head-injury were followed-up with neuropsychological and psycho-educational evaluations. Two cases are presented in detail. Persistent intellectual changes documented on standardized tests were not always apparent to parents or physicians, and recovery of intellectual abilities lagged behind the disappearance of neurological abnormalities. Some of the children required special class placement for several years after the injury. Personality changes were thought to be secondary to stress on impaired perceptual and cognitive abilities, and the desirability of limiting such stress is emphasized.

Object-memory evaluation for prospective detection of dementia in normal functioning elderly: predictive and normative data.

In a prospective study of dementia in initially normal functioning elderly, a brief form of the Fuld Object-Memory Evaluation (OM) was administered to 474 cognitively normal community-residing volunteers aged 75-85 at baseline and annually thereafter. Seventy-two subjects later became demented. Memory test data from the last annual evaluation before cognitive change was noted were available for 56. Although the entire population recalled 7.28 (SD = 1.33) of the 10 objects on Trial 1 of the test at baseline, these 56 subjects recalled only 5.96 (SD = 1.85). When recall of 6 or fewer objects was used as a predictor, the OM test identified 32 of the 56 who subsequently became demented. Compared to an estimated base rate of 15% for dementia, the predictive value of a positive test (PV+) was 39%, and that of a negative test (PV-) was 89%. With a cutoff of 5 or fewer items recalled, the PV+ rose to 59% and the PV- was 94%. Although the OM test was only moderately sensitive to incipient dementia (.57), it was fairly specific (.84), and lowering the cutoff to 5 increased the specificity to .96. Memory testing would therefore seem to hold promise as a predictor of dementia in cognitively normal elderly.

Predicting development of dementia in the elderly with the Selective Reminding Test.

The ability to predict the development of dementia through the detection of memory impairment in nondemented individuals was assessed with the Selective Reminding Test (SR), a popular test of verbal memory functioning in the elderly. The SR was administered to 385 nondemented volunteer subjects (mean age = 80.4 years) enrolled in a longitudinal study of risk factors in the development of dementia. Of these, 36 subjects ultimately became demented. SR scores obtained from 1 to 2 years prior to the diagnosis of dementia were compared with a set of previously established cutoff scores derived from a cognitively normal elderly sample. The results demonstrated that sum of recall and delayed recall were the SR measures best able to predict dementia with sensitivities of 47% and 44%, respectively. The predictive values were 37% and 40%, respectively, or better than two-and-one-half times the base rate. The contributions of both the SR Test and the Fuld Object-Memory Test (OM) were discussed in terms of the further understanding of the characteristics of the preclinical phase of dementia.

Pathological verification of ischemic score in differentiation of dementias.

Fourteen case histories of persons who had a histological diagnosis of either senile dementia of the Alzheimer type, multiinfarct dementia, or a mixed dementia composed of these two types and who showed evidence of a moderate to severe dementia on psychological testing were rated for the presence of thirteen clinical features comprising Hachinski's Ischemic Score. These features are frequently considered primarily characteristic of vascular dementia. Persons with senile dementia of the Alzheimer type were clearly differentiable from persons with multiinfarct dementia and mixed dementia, while the latter two groups were indistinguishable from one another. In our sample, eight features were found to characterize those persons with vascular dementia. These data verify the usefulness of the Ischemic Score in differentiating between senile dementia of the Alzheimer type and vascular dementia.

Intrusions as a sign of Alzheimer dementia: chemical and pathological verification.

Word intrusions, a behavioral abnormality previously observed in experimental subjects receiving anticholinergic medication as well as in patients with Alzheimer dementia (Alz), were studied as a diagnostic indicator of Alz in 29 elderly nursing home residents who later came to autopsy. Those who intruded words from one portion of a mental status test to another tended to have low levels of choline acetyltransferase in the cerebral cortex (median, 104.33,p less than 0.05) and large numbers of cortical senile plaques (median, 16.0,p less than 0.01). Immediate perseverations and "guesses" on a memory test were not counted. In another group of 38 patients referred for clinical neurological examination for dementia, intrusions were associated with Alz in 84% of those who exhibited them and identified 90% of patients with this presumptive diagnosis. Word intrusion appears sufficiently characteristic of Alz to be helpful diagnostically. The association of this behavioral phenomenon with low choline acetyltransferase levels and large numbers of senile plaques suggests that these changes may be important in producing the characteristic behavioral deterioration of Alz.

Oral physostigmine and lecithin improve memory in Alzheimer disease.

Eight patients with early Alzheimer disease were treated with gradually increasing multiple daily doses of oral physostigmine and supplemental lecithin. Six individuals showed improvement in total recall and retrieval from long-term storage (LTR), with a decrease in intrusions (a measure of inaccurate recall). The optimal individual dose was either 2.0 or 2.5 mg of physostigmine for each responding patient. Results of this open trial were subsequently replicated during a double-blind crossover trial comparing physostigmine treatment to placebo. All six patients again demonstrated improvement in total recall and LTR, with a decrease in intrusions. The decrease in intrusions was strongly correlated with increasing inhibition of cholinesterase activity in cerebrospinal fluid, suggesting that the degree of improvement in the patient's memory was related to the amount of physostigmine that reached the brain. Other neurotransmitters and metabolites in cerebrospinal fluid were unaffected by the physostigmine therapy, suggesting a specific effect of physostigmine on the cholinergic system. The results suggest that small oral doses of physostigmine combined with lecithin ingestion have therapeutic benefit for some patients with Alzheimer disease.

Distinguishing normal and demented elderly with the selective reminding test.

The selective reminding (SR) procedure, a popular technique for the study of verbal memory, was used to investigate aspects of memory functioning in a large group of normal elderly and in a smaller group of elderly subjects with Alzheimer Type Dementia (ATD). One hundred thirty-four normal elderly (mean age = 79.53 years) subjects and 21 ATD subjects (mean age = 68.3 years) were administered four versions of the SR test as part of a longitudinal study of risk factors in the development of dementia. Normative data were obtained for multiple components of memory functioning within the elderly sample. Test-retest reliability was .84 for long-term retrieval (LTR), .89 for sum of recall, and .92 for consistent retrieval. Clinical validity studies revealed that the components of sum of recall, storage estimate, LTR, and consistent long-term storage (CLTS) were most valuable in distinguishing mild ATD from normal aging. Positive predictive values ranged from 86% for CLTS, 89% for LTR, 91% for sum of recall, and 100% for storage estimate. These findings suggest that the SR test has considerable clinical utility in differentiating normal aging from dementia, and has promise as a useful tool in the preclinical detection of ATA.

Comparison of rate of annual change of mental status score in four independent studies of patients with Alzheimer's disease.

Longitudinal studies of subjects with autopsy-proven Alzheimer's disease in one skilled nursing home and of clinically diagnosed cases (NINCDS/ADRDA criteria) in three community cohorts are compared with regard to the annual rate of change in the error score of the Blessed information-memory-concentration test (IMC) in which the maximum number of errors possible is 33. The four cohorts differed significantly from each other in regard to age, education, sex, and the degree of dementia as measured by the initial IMC score. Subjects spanned the age range of 52 to 96 years and had 2 to 20 years of education. The rate of change in error score per year was similar whether the initial error score was 0 to 7, 8 to 15, or 16 to 23; however, the rate was reduced when the initial error score was 24 or above, due to a ceiling effect of the test. Among subjects with initial IMC scores less than 24, the annual rate of change varied considerably. However, the mean annual rate of change, 4.4 errors (SD +/- 3.6, SEM +/- 0.3) per year, was independent of residence in a nursing home, location of the study site, and of the patient's sex or education. Of particular importance was the finding that the rate of change in mental test score was independent of age. It can be concluded that the rate of cognitive deterioration in patients with Alzheimer's disease is quite variable among individuals and is independent of the patient's age and whether the patient resides in the community or in a nursing home.(ABSTRACT TRUNCATED AT 250 WORDS)

Dementia and motor neuron disease: morphometric, biochemical, and Golgi studies.

In three patients dementia without neurofibrillary tangles or Pick bodies antedated amyotrophy by several years. The motor neuron disorder in two patients was characterized by terminal bulbar symptoms; in one it was similar to classic amyotrophic lateral sclerosis. In two patients, quantitative studies of selected regions of the cortex using a computerized image analyzer disclosed, as in patients with senile dementia of Alzheimer type, a marked reduction in the number of neurons, especially those larger than 90 mu 2. The findings differed from those in Alzheimer dementia, however, in that the cells in the substantia innominata were not reduced and the levels of choline acetyltransferase and somatostatin-like immunoreactivity, determined in one patient, were within normal limits. A variable degree of sponginess of the upper layers of the cortex was attributed to attrition of pyramidal cell dendrites, observed in the one patient in whom Golgi study was successful. Because of severe degeneration of the substantia nigra in all three, the disease in these patients may represent a subset of motor neuron disease or a multisystem atrophy.