A NEUROLOGICAL BASIS FOR GULF WAR SYNDROME?

Evidence to support the neurologic basis of Gulf War syndrome is presented in a study in the September Archives of Neurology.The authors describe an association between reduced functioning neuronal mass in the basal ganglia and the brainstem and increased central dopamine function in Gulf War veterans.

"This finding gives increased importance to our earlier brain scan evidence of brain damage in these veterans," said Robert Haley, MD, lead author and Professor of Internal Medicine at the University of Texas Southwestern Medical Center at Dallas. "Showing that the degree of brain cell injury directly affects the level of brain dopamine production suggests that the brain damage may be having a real effect on these veterans' brain function and is not just a coincidental finding."

Functioning neuronal mass was assessed in 12 veterans with Haley Gulf War syndrome symptom complex 2 ("confusion-ataxia") and in 15 healthy veterans of similar age, sex, and education level. The subjects underwent magnetic resonance (MR) spectroscopy of the brain to measure levels of N-acetyl-aspartate, choline, and creatinine. Gulf War veterans had a lower functioning neuronal mass in both the left and the right basal ganglia than did controls, found the authors.

Although reduced functional mass of the left basal ganglia was associated with increased dopamine production, reduced functional mass of the right basal ganglia was not. Dopamine activity was assessed by calculating the ratio of plasma homovanillic acid (HVA) to 3-methoxy-4-hydroxyphenylglycol (MHPG). The laterality of dopamine activity is supported by previous studies in rodents, the authors said. In rats, unilateral lesions of dopaminergic pathways in the left hemisphere sharply increase dopamine metabolism in both hemispheres, while unilateral lesions on the right have less effect.

The authors described negative and positive implications of their findings. "We hypothesize that with injury to the brain cells that normally control dopamine production, the cells at first go wild, overproducing dopamine," said co-author Frederick Petty, MD, Professor of Psychiatry at the University of Texas Southwestern Medical Center, and a staff psychiatrist at the Dallas Veterans Affairs Medical Center. "The question is whether, over time, these overstimulated cells will wear out and die. If so, these patients could develop Parkinson's disease." A positive implication of the study is that measurements of functioning neuronal mass by MR spectroscopy and of central dopamine function by peripheral blood testing facilitate the study of Gulf War syndrome symptom complexes, added the authors.

"The findings…offer the first biochemical substantiation of the [Persian Gulf War] syndrome, and transcend the syndrome by offering insights into potential mechanisms underlying confusional syndromes and Parkinson disease," said Roger N. Rosenberg, MD, Chief Editor of Archives of Neurology,in an accompanying editorial. "These findings also offer insights into the potential pharmacological treatment of patients with PGW syndrome," he concluded.

Suggested Reading
1. Haley RW, Fleckenstein JL, Marshall, WW, et al. Effect of basal ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic resonance spectroscopy and plasma homovanillic acid levels. Arch Neurol.2000;57:1280-1285.
2. Rosenberg RN. Defining the neurological basis of the Gulf War syndrome. Arch Neurol.2000;57:1263.

CARDIAC SYMPATHETIC DENERVATION IN PARKINSON'S DISEASE

Cardiac sympathetic denervation is characteristic of most patients with Parkinson's disease—and all patients with Parkinson's disease and sympathetic neurocirculatory failure—according to the authors of a study in the September 5 Annals of Internal Medicine. As cardiac sympathetic denervation is associated with Parkinson's disease, not multiple-system atrophy, the authors suggest it may be useful in the differential diagnosis of these two conditions.

The study cohort included 29 patients with Parkinson's disease, 10 of whom had never received levodopa, and 24 patients with multiple-system atrophy, eight of whom were taking levodopa at evaluation. These patients were compared with seven patients with pure autonomic failure and with 33 controls. Twenty-two of the controls had a history of neurocardiogenic syncope, and 11 had a history of postural tachycardia syndrome.

Data from positron emission tomography scans (following injection of 6-[18F]fluorodopamine) and neurocardiac measurements were used to answer five questions: 1) What proportions of patients with Parkinson disease, with or without sympathetic neurocirculatory failure, have decreased myocardial 6-[18F]fluorodopamine-derived radioactivity? 2) Does decreased myocardial 6-[18F]fluorodopamine-derived radioactivity in Parkinson's disease actually reflect cardiac sympathetic denervation, as identified by indices of cardiac norepinephrine release, neuronal uptake, turnover, and synthesis? 3) Does the frequency of cardiac sympathetic denervation differ between groups of patients with Parkinson disease who have sympathetic neurocirculatory failure and those who do not? 4) Does cardiac sympathetic denervation also occur in patients with multiple-system atrophy, a progressive neurodegenerative disease of adults that features autonomic dysfunction and has parkinsonian, cerebellar, or mixed forms? (The diagnosis of multiple-system atrophy is clinical and, except for a typically poor response to levodopa treatment, can be difficult to distinguish from Parkinson disease) 5) Is cardiac sympathetic denervation in patients with Parkinson disease related to levodopa treatment or to disease duration or severity?

No association between levodopa and sympathetic neurocirculatory failure was found, reported the authors.

The authors suggested that decreased myocardial 6-[18F]fluorodopamine—derived radioactivity may be a more sensitive test for loss of sympathetic terminal innervation in Parkinson's disease than clinical physiologic changes. They also suggested that the pathogenesis of sympathetic neurocirculatory failure in patients with Parkinson's disease may include the loss of sympathetic terminal innervation. The loss of catecholamine innervation in Parkinson's disease occurs in the nigrostriatal system in the brain and in the sympathetic nervous system in the heart, concluded the authors.

Suggested Reading
Goldstein DS, Holmes C, Li S-T, et al. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med.2000;133:338-347.

FIRST EVIDENCE OF RECESSIVE GENE IN ALZHEIMER'S DISEASE DISCOVERED

Researchers speculate that an autosomal recessive gene exists for Alzheimer's disease. According to a report in the September 12 Neurology,an unusually high rate of the disease in an Arab community was not caused by a high incidence of the apolipoprotein E, APOE*E4, allele. In fact, APOE*E4 showed up in this population at the lowest level on record, according to neurologist Amos Korczyn, MD, MSc, of Tel Aviv University in Israel.

In a recent population-based study, elderly residents of an Arab community in Wadi Ara, northern Israel, were screened by Israeli researchers and neurologist Robert Friedland, MD, of the Alzheimer's Center at Case Western Reserve University and the University Hospital of Cleveland. Of the 821 people, 60.5% of those over age 85 had Alzheimer's disease, and 20% of those over 65 had Alzheimer's disease, which is compared to rates of about 40% and 10%, respectively, found in other populations. These rates were adjusted for age, education, and gender.

The APOE*E4 allele frequency in the Wadi Ara population was examined, and DNA samples were taken from 256 randomly selected study participants (mean age, 75 ± 9 years; 118 male), and their APOE genotype was determined by a PCR-based method. The APOE*E4 allele was found to be carried by 22 of the 256 cases examined (all heterozygous), including 3/34 with Alzheimer's disease (APOE*E4 allele frequency 0.04), 8/128 nondemented elderly subjects (APOE*E4 allele frequency 0.03), 7/56 with age-associated memory impairment (APOE*E4 allele frequency 0.06), and 4/38 with other types of dementia and pseudodementia (APOE*E4 allele frequency 0.04).

Only 4% of subjects in the Wadi Ara study carried the allele; in other populations, approximately 15% of people carry the allele. While APOE*E4's association with cognitive decline—as reported in other populations—cannot yet be excluded, it cannot explain the high Alzheimer's disease prevalence in this population, the authors noted.

As 44% of all Arab marriages in Israel are consanguineous, with a mean inbreeding coefficient of 0.192, the researchers speculate that recessive genes for Alzheimer's exist and are responsible for the high Alzheimer's disease prevalence in Wadi Ara. "We are hunting for this gene now," Dr. Korczyn said. "Identifying the gene would likely have a major impact on our understanding of how and why Alzheimer's occurs. We would also then need to look at whether the gene is involved in causing Alzheimer's disease in other populations."

"This population is ideal for studying the role of recessive genes in Alzheimer's and other diseases because of the large family size and the amount of intermarrying," said Dr. Friedland. The researchers are also investigating whether environmental factors play a role in the high rate of Alzheimer's disease in this population.

Suggested Reading
Bowirrat A, Friedland RP, Chapman J, et al. The very high prevalence of AD in an Arab population is not explained by APOE*E4 allele frequency. Neurology.2000;9:731.

CEREBROVASCULAR MEDICATIONS MAY LOWER RISK OF MENTAL DECLINE

Cerebrovascular disease medications, and antihypertensives in particular, may reduce or prevent cognitive impairment, and possibly dementia and Alzheimer's disease in older patients. However, data presented in a study in the September Journal of the American Geriatrics Societyalso suggest that physicians should be cautious in prescribing antihypertensive drugs with centrally acting sympatholytic properties for these patients.

Researchers from the University of Pittsburgh and the Indiana University School of Medicine found that a wide range of drugs given to reduce the risk of cerebrovascular disease—including antihypertensive, antidiabetic, antihyperlipidemics, and antithrombotic agents—also reduce the risk of intellectual and functional decline.

The longitudinal study was conducted in a community-based random sample of 2,212 African Americans age 65 or older and at high risk for cerebrovascular disease. Seventy-seven percent of the population had at least one vascular risk factor, including stroke.

Four sets of outcome measures were defined by diagnostic criteria: cognitive impairment as defined by the subjects' performance on the Community Screening Instrument for Dementia (CSID) cognitive scale; cognitive/functional impairment as defined by the total CSID score; dementia or normal diagnosis as defined by both Diagnostic and Statistical Manual, Revised Third Edition and International Statistical Classification of Diseases, 10th Revisioncriteria; and diagnosis of Alzheimer's disease according to NINCDS-ADRDA criteria.

When examined together, the vascular risk factor—mediating medications (antihypertensives, antidiabetics, antihyperlipidemics, and antithrombotics) were associated with a significantly reduced risk of cognitive impairment after controlling for age, education, and stroke (OR, 0.73). The data also showed a significantly reduced risk of cognitive/functional impairment (OR, 0.66). Subjects taking the drugs had lower rates of Alzheimer's disease and other specific forms of dementia, although there were too few cases to confirm a significant reduction, the researchers reported.

The antihypertensive medications in particular were associated with a significantly reduced risk of cognitive impairment (OR, 0.66) and cognitive/functional impairment (OR, 0.61).

The researchers also found that certain antihypertensive agents, such as centrally acting sympatholytic drug methyldopa, were associated with impaired cognition (OR, 2.24) but not with increased risk of cognitive/functional impairment.

The authors plan follow-up studies to clarify the long-term effects of risk-factor—reducing drugs.

Suggested Reading
Richards SS, Emsley CL, Roberts J, et al. The association between vascular risk factor-mediating medications and cognition and dementia diagnosis in a community-based sample of African-Americans. J Am Geriatr Soc. 2000;48:1035-1041.

PARKINSON'S DISEASE DRUG MAY HELP FIGHT MAJOR DEPRESSION

Pramipexole, currently approved for use in Parkinson's disease, has also been shown to be effective and safe as a treatment for depression. The drug may be a useful therapy for patients with depressive illness or, in combination with selective serotonin reuptake inhibitors, for refractory depression.

In a research article in Depression and Anxiety,the authors describe a double-blind, randomized, placebo-controlled, parallel-group clinical trial using fixed doses of pramipexole and fluoxetine. One hundred seventy-four patients with a Diagnostic and Statistical Manual, Revised Third Editiondiagnosis of major depression (single or recurrent episode, with or without melancholia, and without psychotic features) were assigned to one of five treatment groups: placebo, fluoxetine (20 mg), or one of three pramipexole groups (0.375 mg, 1.0 mg, and 5.0 mg). Patients received a one-week placebo run-in, eight weeks of treatment (beginning with titration for the 1.0 and 5.0 mg pramipexole patients), and a one-week post-study follow-up assessment.

Patients were evaluated using the Hamilton Psychiatric Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinician's Global Impressions-Severity of Illness scale (CGI-SI). Results indicated that by endpoint (week 8), patients receiving pramipexole at the 1.0 mg per day dose had significant improvement over baseline compared with the placebo group by measure of the HAM-D (–13.26), MADRS (–17.26), and the CGI-SI (–1.83). The most obvious improvement was seen in the pramipexole 5.0 mg group, although a substantial dropout rate for this group precluded statistical tests versus placebo late in the study. Patients taking fluoxetine also showed significant improvements at end point on the MADRS and earlier in the study on the HAM-D.

Although no direct comparison to fluoxetine was conducted, pramipexole 1.0 mg (and particularly pramipexole 5 mg, in those patients who could tolerate it) provided similar or more statistically consistent improvement than fluoxetine 20 mg, when both were compared with placebo.

Suggested Reading
Corrigan MH, Denahan AQ, Wright CE, et al. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety.2000;11:58-65.

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