Pain, fatigue, and sleep in eosinophilia-myalgia syndrome: relationship to neuropsychological performance.

Cognitive problems are frequently reported in patients with eosinophilia-myalgia syndrome (EMS). This is the first study to explore, in EMS, the relationship between specific neuropsychological deficits and fatigue and pain. Relationships among depression, sleep disturbance, and neuropsychological deficits in EMS were also examined. Neither fatigue nor pain was correlated with memory impairment. Sleep disturbance was significantly correlated with verbal memory impairment, but not with deficits in visuospatial memory. These results suggest that cognitive loss in EMS cannot be attributed to pain or fatigue. Although some aspects of memory impairment may be associated with disturbed sleep, visual memory deficits are clearly independent of sleep deficits and may result from direct effects of the disease on the central nervous system.

The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis.

BACKGROUND: Amantadine hydrochloride and pemoline, both frequently used to treat the fatigue of multiple sclerosis (MS), may also improve attention and other cognitive functions in MS. To our knowledge, these agents have never been compared in a placebo-controlled trial of patients with MS. OBJECTIVE: To evaluate the effects of amantadine and pemoline on cognitive functioning in MS. METHODS: A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine, pemoline, or placebo using a parallel group design. They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning. Primary outcome measures were tests of attention (Digit Span, Trail Making Test, and Symbol Digit Modalities Test), verbal memory (Selective Reminding Test), nonverbal memory (Benton Visual Retention Test), and motor speed (Finger Tapping Test). RESULTS: Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment. All three treatment groups improved on tests of attention (P < .003), verbal memory (P < .001), and motor speed (P < .002). There were no significant differences between amantadine, pemoline, and placebo. CONCLUSIONS: Cognitive functioning in MS is independent of fatigue. Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo.

Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons.

Identification of elderly individuals with low and high risk for future dementia has emerged as an important clinical and public health issue. To address this issue, we assessed neuropsychological performance in 317 initially nondemented elderly persons between 75 and 85 years of age and followed them for at least 4 years as part of the Bronx Aging Study. Four measures of cognitive function from the baseline assessment (delayed recall from the Buschke Selective Reminding Test, recall from the Fuld Object Memory Evaluation, the Digit Symbol subtest from the Wechsler Adult Intelligence Scale, and a verbal fluency score) can identify one subgroup with an 85% probability of developing dementia over 4 years and another with a 95% probability of remaining free of dementia. The model achieved an overall positive predictive value of 68%, or three times the base rate, for prediction of the development of dementia in our sample. The overall negative predictive value for prediction of absence of dementia was 88%. Baseline measures of cognitive function, often performed many years before the actual diagnosis of dementia, can provide important information about dementia risk. The group likely to develop dementia becomes a target for preventive or early therapeutic interventions, and the group unlikely to develop dementia can be reassured.

Cognitive functioning and depression in patients with chronic fatigue syndrome and multiple sclerosis.

OBJECTIVE: To assess cognitive function in patients with chronic fatigue syndrome (CFS) and multiple sclerosis (MS) and to evaluate the role of depressive symptoms in cognitive performance. DESIGN: Case-control. All subjects were given a neuropsychological battery, self-report measures of depression and fatigue, and a global cognitive impairment rating by a neuropsychologist "blinded" to clinical diagnosis. Patients with MS and CFS were additionally evaluated with a Structured Clinical Interview for DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition) disorders. SETTING: Institutional and private neurological practices and the community at large. PATIENTS: Twenty patients with CFS diagnosed in accord with the Centers for Disease Control and Prevention-revised criteria who had cognitive complaints; 20 patients with clinically definite MS who were ambulatory and were matched for fatigue severity, age, and education to CFS subjects; and 20 age- and education-matched healthy controls. RESULTS: Patients with CFS had significantly elevated depression symptoms compared with patients with MS and healthy controls (P < .001) and had a greater lifetime prevalence of depression and dysthymia compared with MS subjects. Patients with CFS, relative to controls, performed more poorly on the Digit Symbol subtest (P = .023) and showed a trend for poorer performance on logical memory (P = .087). Patients with MS compared with controls had more widespread differences of greater magnitude on the Digit Span (P < .004) and Digit Symbol (P < .001), Trail Making parts A (P = .022) and B (P = .037), and Controlled Oral Word Association (P = .043) tests. Patients with MS also showed a trend of poorer performance on the Booklet Category Test (P = .089). When patients with CFS and MS were directly compared, MS subjects had lower scores on all measures, but the differences reached significance only for the Digit Span measure of attention (P = .035). CONCLUSIONS: Patients with CFS compared with MS have more depressive symptoms but less cognitive impairment. Relative to controls, a subset of CFS subjects did poorly on tests of visuomotor search and on the logical memory measure of the Wechsler Memory Scale-revised. Poor performance of logical memory in CFS appears to be related to depression, while visuomotor deficits in CFS are unrelated. Cognitive deficits in patients with MS are more widespread compared with those in patients with CFS and are independent of depressive symptoms.

Neurocognitive dysfunction in the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome (EMS), a multisystem disorder associated with ingestion of L-tryptophan-containing products, causes sclerodermatous skin changes, cardiopulmonary disease, and a range of peripheral neurologic complications. Many EMS patients also report cognitive difficulty in association with the disease. To determine the frequency of objective neurocognitive impairment in EMS patients with subjective complaints of cognitive difficulty and to assess the relationship of neurocognitive loss with demographic features, degree of peripheral eosinophilia, and psychiatric diagnosis, we compared 24 EMS patients with 32 age- and education-matched healthy controls, using a comprehensive neuropsychological test battery. EMS patients additionally underwent a psychiatric interview and rheumatologic evaluation. Sixty-two percent (15 of 24) of the EMS patients demonstrated neurocognitive deficits. Compared with healthy controls, EMS patients demonstrated significant impairment on tests of verbal memory, visual memory, conceptual reasoning, and motor speed. Cognitively impaired EMS patients did not differ from those without cognitive impairment on demographic markers, degree of peripheral eosinophilia, presence of peripheral neuropathy, or frequency of concurrent psychiatric disorder, including major depression. These data support the hypothesis that EMS is associated with an encephalopathy in addition to its previously recognized peripheral neuropathy and other rheumatologic manifestations.

Identification of normal and pathological aging in prospectively studied nondemented elderly humans.

Results of a standardized histochemical and immunocytochemical analysis of the brains of 14 nondemented elderly humans for whom prospective neurological and neuropsychological data had been collected for 3 to 8 years before death suggested that nondemented elderly humans fall into two pathological subgroups that are not clinically distinguishable. One was associated with moderate to marked cerebral amyloid deposition ("pathological aging"), while the other had either minimal or no amyloid deposition ("normal aging"). Neocortical and hippocampal neurofibrillary degeneration was either completely absent or of very limited degree in both subgroups. Both subgroups had ubiquitin-immunoreactive dystrophic neurites in the cerebral cortex and granular degeneration of myelin in white matter. These ubiquitin-immunoreactive structures seem to be a universal and invariant manifestation of brain aging, but the same cannot be said for amyloid deposition and neurofibrillary degeneration. Pathological aging might be preclinical Alzheimer's disease, but it currently cannot be distinguished from normal aging by even sensitive neuropsychological measures. These findings provide strong support for the hypothesis that cerebral amyloid deposition is not necessarily associated with clinically apparent cognitive dysfunction and that additional factors, such as neuronal or synaptic loss or widespread cytoskeletal aberrations, are necessary for dementia in AD.

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.

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.

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.

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.