Recurrent neural network-based approach for early recognition of Alzheimer's disease in EEG.

OBJECTIVE: We explored the ability of specifically designed and trained recurrent neural networks (RNNs), combined with wavelet preprocessing, to discriminate between the electroencephalograms (EEGs) of patients with mild Alzheimer's disease (AD) and their age-matched control subjects. METHODS: Twomin recordings of resting eyes-closed continuous EEGs (as well as their wavelet-filtered subbands) obtained from parieto-occipital channels of 10 early AD patients and 10 healthy controls were input into RNNs for training and testing purposes. The RNNs were chosen because they can implement extremely non-linear decision boundaries and possess memory of the state, which is crucial for the considered task. RESULTS: The best training/testing results were achieved using a 3-layer RNN on left parietal channel level 4 high-pass wavelet subbands. When trained on 3 AD and 3 control recordings, the resulting RNN tested well on all remaining controls and 5 out of 7 AD patients. This represented a significantly better than chance performance of about 80% sensitivity at 100% specificity. CONCLUSION: The suggested combined wavelet/RNN approach may be useful in analyzing long-term continuous EEGs for early recognition of AD. This approach should be extended on larger patient populations before its clinical diagnostic value can be established. Further lines of investigation might also require that EEGs be recorded from patients engaged in certain mental (cognitive) activities.

A multiple sclerosis cluster associated with a small, north-central Illinois community.

The authors investigated a reported incidence cluster of multiple sclerosis (MS) cases in a small, north-central Illinois community to determine validity and statistical significance. DePue, Illinois--a small, north-central Illinois community--has previously been the site of significant environmental heavy-metal exposure from a zinc smelter. Significant contamination of soil and water with zinc and other metals has been documented in this community during the time period of interest. In the mid-1990s, several cases of MS were reported to the Illinois Department of Public Health within the geographic limits of this community. Available medical records from purported MS cases reported to the Illinois Department of Public Health were reviewed, and living individuals were seen and examined. Statistical analyses were conducted with clinically definite MS cases; onset dates were determined by first symptom, and expected incidence rates were determined from published epidemiologic studies. Nine new cases of clinically definite MS occurred among residents of DePue, Illinois, during the period between 1971 and 1990. Seven of the 8 living subjects included in the final analyses were examined by one author (RS). The computed incidence rate deriving from these cases within DePue Township, Illinois, represented a statistically significant excess of new MS cases over expected. During the period from 1971 through 1990, a significant excess of MS cases occurred within the population of DePue, Illinois. Significant exposure of this population to mitogenic trace metals, including zinc, was also documented during this time period.

Parkinson's disease: a preliminary study of yohimbine challenge in patients with anxiety.

In this pilot study, we performed an oral yohimbine challenge in 6 patients with Parkinson's disease (PD) and anxiety or depression, 2 parkinsonian patients without psychiatric illness, and 2 healthy control subjects to determine whether patients with Parkinson's disease and anxiety respond to this adrenergic agent in the same way patients with idiopathic anxiety disorders respond. Given the atypical nature of depression in Parkinson's disease (characterized by prominent anxiety), we also wanted to see if patients with Parkinson's disease and depression (but no history of anxiety) are susceptible to yohimbine-induced panic. Parkinsonian patients with anxiety developed panic attacks at frequencies comparable to primary psychiatric patients with panic disorder. The one patient with PD and a history of major depression alone developed a panic attack. Regardless of their history of anxiety or depression, parkinsonian patients demonstrated a vulnerability to yohimbine-induced somatic symptoms.

Neuropsychologic status in multiple sclerosis after treatment with glatiramer.

BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.

Lewy body disease: can we diagnose it?

The authors assessed the accuracy of published clinical criteria and their own modifications of those criteria in diagnosing Lewy body disease (LBD). Clinical diagnoses were made by two clinicians, blinded to neuropathologic diagnoses, using the Rochester Alzheimer's Disease Center database and traditional medical records. Neuropathologic diagnoses were made according to published guidelines. Results from 21 Alzheimer's disease and 18 LBD patients indicated that no set of clinical criteria was accurate in diagnosing LBD. The only significant predictor of LBD in this population was depression, which was more common in LBD than in Alzheimer's disease. The authors conclude that clinical identification of LBD is an important but unresolved neurological problem.

A review of Lewy body disease, an emerging concept of cortical dementia.

Dementia associated with cortical Lewy bodies on neuropathologic examination may comprise the second largest category of age-related cognitive impairment, after Alzheimer's disease. Despite its prevalence, a consensus has not yet been reached regarding the terminology, neuropathologic criteria, or clinical symptomatology of this postulated nosologic entity. Lewy body disease (LBD) is beginning to be diagnosed clinically in neuropsychiatric clinics, but universally accepted diagnostic criteria for LBD remain to be validated. In this article the authors review the literature on LBD, including both neuropathologic and clinical findings.

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Psychiatric features in diffuse Lewy body disease: a clinicopathologic study using Alzheimer's disease and Parkinson's disease comparison groups.

We conducted a retrospective study to determine the frequency of depression, hallucinations, and delusions in patients with diffuse Lewy body disease (DLBD) and to compare these findings with those in Alzheimer's disease (AD) and Parkinson's disease (PD). One hundred twelve subjects were included in the study. Of these, 28 subjects were diagnosed with DLBD, 58 with AD, and 26 with PD at autopsy. Main outcome measures included the percentages of subjects in each of the three categories in whom depression, hallucinations, or delusions were reported at any time during the course of the illness. Hallucinations and delusions were further classified by type. We found that depression was more common in DLBD (50.0%) than in AD (13.8%) (chi 2 = 13.00, p = 0.0003). There was no difference in the frequency of depression in DLBD and PD (57.7%) (chi 2 = 0.32, p = 0.57). Hallucinations were reported more frequently in DLBD (60.7%) than in AD (34.5%) (chi 2 = 5.30, p = 0.021). There was no difference in the frequency of hallucinations in DLBD and PD (53.8%) (chi 2 = 0.26, p = 0.61). Delusions were more common in DLBD (57.1%) than in PD (15.4%) (chi 2 = 10.08, p = 0.0015). There was no difference in the frequency of delusions in DLBD and AD (53.4%) (chi 2 = 0.10, p = 0.75). There was a male predominance of DLBD cases and PD cases; AD cases were predominantly women. We conclude that psychiatric features are very common in DLBD and should be a central diagnostic criterion for the disease.

Anxiety and Parkinson's disease.

Anxiety disorders, particularly generalized anxiety, panic, and social phobia, occur in up to 40% of patients with Parkinson's disease (PD). This rate is higher than in normal or other disease comparison populations. Current evidence suggests that anxiety may not be a psychological reaction to the illness but rather may be linked to specific neurobiologic processes accompanying PD. Anxiety in PD often coexists with depression. The optimal pharmacologic treatment for anxiety in patients with PD has not been established, but available information about the use of anxiolytics in PD is reviewed. Further study of the relationship between anxiety and PD may provide an excellent opportunity to clarify the neurobiologic substrate of anxiety itself.

Conditioning of cyclophosphamide-induced leukopenia in humans.

This study evaluated whether decrements in peripheral leukocyte counts induced by cyclophosphamide can be conditioned in humans. Ten subjects being treated for multiple sclerosis received four intravenous treatments with cyclophosphamide (unconditioned stimulus) paired with a conditioned stimulus. Subjects received conditioned stimulus plus 10 mg of cyclophosphamide during one of the next two treatments in a double-blind manner. Eight of 10 subjects (P = 0.044) displayed decreased peripheral leukocyte counts following conditioned stimulus. This change may have resulted from classical conditioning processes.

Incorrect diagnosis of Alzheimer's disease. A clinicopathologic study.

OBJECTIVES: To examine the accuracy of clinical diagnoses of Alzheimer's disease (AD) in subjects enrolled in the Rochester Alzheimer's Disease Project (RADP) who were examined at autopsy, and to present a list of clinical "red flags." DESIGN: Autopsy examination of both prospective and retrospective subjects consecutively enrolled in this clinicopathologic study of the RADP. SETTING: University hospital and research center, using a multidisciplinary geriatric neurology clinic, satellite clinics, nursing home visits, and home visits. PATIENTS: One hundred seventy subjects clinically diagnosed as having AD who were enrolled in the RADP between 1983 and 1993 underwent neuropathologic examination. Of these, 93 had been enrolled prospectively and 77 retrospectively. MAIN OUTCOME MEASURES: Agreement between clinical and pathologic diagnoses. RESULTS: One hundred forty-nine subjects of 170 clinically diagnosed as having AD fulfilled the pathologic criteria for AD, yielding an accuracy rate of 88%. Of 93 subjects enrolled prospectively and diagnosed as having AD, 83 (90%) met the histologic criteria for AD. Of the 77 subjects enrolled retrospectively, neuropathologic examination indicated definite AD in 66 (86%). CONCLUSIONS: There was a high correlation between clinicians' diagnoses and final pathologic diagnoses. The most common clinical errors involved the misdiagnosis of dementias due to Parkinson's disease and cerebrovascular disease. There was no significant difference in the accuracy rates of subjects enrolled prospectively and retrospectively.

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

A genetic marker and family history study of the upstate New York multiple sclerosis cluster.

We report nine additional cases of new-onset multiple sclerosis (MS) among employees of an upstate New York manufacturing plant that uses zinc as a primary metal. These cases, identified during the decade 1980 to 1989, had clinical onset of the disease between 1979 and 1987. The new cases confirm the increased incidence of MS previously reported in the plant population for the 1970 to 1979 decade. The MS subjects in this occupationally based cluster do not seem different from other MS patients with regard to rates of familial MS or the frequencies of alleles for human leukocyte (HLA-DR) antigens or transferrin. The frequency distribution of alleles for transferrin (an iron- and zinc-binding protein) may differ in these and other MS subjects compared with controls.

Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group.

OBJECTIVE: Magnetic resonance imaging, computed tomography, cerebrospinal fluid analysis, and evoked potential testing are used to assist in the diagnosis of patients suspected to have multiple sclerosis (MS). The impact of these tests on a clinician's diagnosis of patients suspected to have MS has not been studied systematically. DESIGN: Clinicians made a diagnosis of each patient following clinical evaluation, again after reviewing the results of magnetic resonance imaging, and finally after reviewing information from other laboratory testing. These diagnoses were compared with the criterion standard of a masked "gold standard" panel reviewing all information after a mean follow-up of 0.9 year. SETTING: The General Neurology Clinic and Multiple Sclerosis Clinic of the University of Rochester (NY). PATIENTS: A consecutive sample of 62 patients diagnosed as having either possible or probable MS following clinical evaluation. MAIN OUTCOME MEASURE: Changes in diagnostic certainty of clinicians following incremental presentation of new laboratory data and the accuracy of such diagnoses. RESULTS: Clinicians used magnetic resonance imaging findings to diagnose definite MS or to eliminate MS from diagnostic consideration in 44% of cases. In these cases, further laboratory testing did not alter clinicians' decisions. In the remaining 56% of cases, in which magnetic resonance imaging did not lead to a diagnosis of definite MS or eliminate MS from diagnostic consideration, further laboratory testing led to such diagnoses in an additional 13% of cases. Gold standard diagnoses were in agreement with the clinician's assessments. CONCLUSIONS: Magnetic resonance imaging aids in the evaluation of patients suspected to have MS; other subsequent studies (computed tomography, cerebrospinal fluid analysis, and evoked potential testing) have less impact. After all studies are performed, about half of such patients still have a tentative diagnosis.

Perils and pitfalls of magnetic resonance imaging in the diagnosis of multiple sclerosis. The Rochester-Toronto MRI Study Group.

Purpose. Magnetic resonance imaging (MRI) has come to assume a position of major importance in the diagnostic process for multiple sclerosis (MS). The authors believe that a tendency toward overreliance on MRI results in isolation from clinical findings continues to result in both false-positive and false-negative diagnostic errors. Methods. To evaluate this, MRI results in newly referred patients with clinical findings suggestive, but not diagnostic, for MS, were studied prospectively. Results. Of 99 consecutive referrals for suspected MS, there were 3 false-positive diagnoses of MS and 7 false-negatives, when the MRIs were read in isolation from specific clinical data. None of the scans in the false-negative groups were normal. Representative images of both groups are provided. Conclusion. In newly referred patients who fall short of criteria for definite MS, it remains dangerous for both clinicians and radiologists to rely too heavily only on MRI results.

The effects of exposure to dietary nickel and zinc upon humoral and cellular immunity in SJL mice.

We are interested in potential interactions between environmental trace metal exposures and immune function. In particular, we have wondered whether dietary exposure to nickel and zinc cations can influence T and B cell proliferation and function. To study this question, we fed SJL female mice supplemental nickel and zinc sulfate from 4-8 weeks of age, and immunized the animals intraperitoneally (i.p.) with keyhole limpet hemocyanin (KLH) at 8 weeks. Eight days later, we measured antibody responses to KLH. Both IgG and IgM antibody responses to KLH were significantly depressed in vivo in the nickel fed animals (p less than 0.005). In vitro antigenic responsiveness to KLH of splenocytes from nickel fed animals was also depressed compared with control and zinc supplemented animals (p less than 0.002). This altered antigenic responsiveness persisted even after cells had been cultured for 5 days in standard media. The zinc supplemented diets did not seem to affect antibody responsiveness and proliferation. The proliferative responses of B cells to the mitogen lipopolysaccharide (LPS) were significantly depressed in Ni fed mice, but were not affected in the zinc fed animals. T cell mitogenic responses to concanavalin A were not affected in the nickel fed animals, and were enhanced in zinc fed animals. We conclude that dietary exposure to certain trace metals may induce persisting alterations in immunity in this animal model.