Melville R. Klauber

A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease

BACKGROUND There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimers disease. METHODS We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimers disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). RESULTS Despite random assignment, the baseline score on the Mini-Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the primary outcome (P<0.001). In the unadjusted analyses, there was no statistically significant difference in the outcomes among the four groups. In analyses that included the base-line score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline (median time, 655 days; P=0.012), alpha-tocopherol (670 days, P=0.001) or combination therapy (585 days, P=0.049), as compared with the placebo group (440 days). CONCLUSIONS In patients with moderately severe impairment from Alzheimers disease, treatment with selegiline or alpha-tocopherol slows the progression of disease.

The role of secondary brain injury in determining outcome from severe head injury

As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

The prevalence of peripheral arterial disease in a defined population.

Because patients with peripheral arterial disease (PAD) may be asymptomatic or may present with atypical symptoms or findings, the true population prevalence of PAD is essentially unknown. We used four highly reliable, sophisticated noninvasive tests (segmental blood pressure, flow velocity by Doppler ultrasound, postocclusive reactive hyperemia, and pulse reappearance half-time) to assess the prevalence of large-vessel PAD and small-vessel PAD in an older (average age 66 years) defined population of 613 men and women. A total of 11.7% of the population had large-vessel PAD on noninvasive testing, and nearly half of those with large-vessel PAD also had small-vessel PAD (5.2%). An additional 16.0% of the population had isolated small-vessel PAD. Large-vessel PAD increased dramatically with age and was slightly more common in men and in subjects with hyperlipidemia. Isolated small-vessel PAD, by contrast, was essentially unrelated to sex, hyperlipidemia, or age, although it was somewhat less common before age 60. Intermittent claudication rates in this population were 2.2% in men and 1.7% in women, and abnormalities in femoral or posterior tibial pulse were present in 20.3% of men and 22.1% of women compared with the noninvasively assessed large-vessel PAD rate of 11.7%. Thus assessment of large-vessel PAD prevalence by intermittent claudication dramatically underestimated the true large-vessel PAD prevalence and assessment by peripheral pulse examination dramatically overestimated the true prevalence.

The Lewy body variant of Alzheimer's disease: A clinical and pathologic entity

Thirty-six clinically diagnosed and pathologically confirmed Alzheimers disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.

The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral arterial disease: results from noninvasive testing in a defined population.

In a companion article we have reported the prevalence, in an older, defined population, of traditional assessments (intermittent claudication and abnormal pulse examination) of peripheral arterial disease (PAD) as compared with the results of highly accurate noninvasive testing. In this article we report the sensitivity, specificity, and positive and negative predictive values for claudication and abnormal pulses for the diagnosis of large-vessel and small-vessel PAD as determined by noninvasive testing. Claudication and abnormal pulses were completely unrelated to isolated small-vessel PAD. In contrast, both claudication and abnormal pulses were significantly correlated with large-vessel PAD. Claudication and an abnormal femoral pulse showed a high specificity and positive predictive value but a low sensitivity for large-vessel PAD. Conversely, an abnormal dorsalis pedis pulse showed a good sensitivity but low specificity and positive predictive value. The best single discriminator was an abnormal posterior tibial pulse, which had high sensitivity, specificity, and positive predictive value. Various combinations of claudication and pulse abnormalities revealed a good sensitivity for broader criteria but at the expense of specificity, whereas stricter criteria had a good specificity and positive predictive value but a poor sensitivity. No combination was superior to an abnormal posterior tibial pulse alone.(ABSTRACT TRUNCATED AT 250 WORDS)

The correlation between symptoms and non-invasive test results in patients referred for peripheral arterial disease testing.

The WHO/Rose questionnaire has served as the epidemiologic and clinical standard in the assessment of leg pain in patients with peripheral arterial disease (PAD) for over three decades. However, the structure of this questionnaire does not allow assessment of leg-specific (i.e. right versus left) symptoms. We studied 508 patients aged 39–95 years (mean 68 years), initially referred for PAD non-invasive testing. A revised questionnaire, the San Diego Claudication Questionnaire, was administered which allowed determination of leg-specific symptoms and evaluated thigh and buttock as well as calf pain. Leg-specific symptoms were categorized into no pain, pain at rest, non-calf claudication, non-Rose calf claudication, and Rose claudication. At the same visit, the ankle brachial index, the toe brachial index, and peak posterior tibial flow velocity were measured by Doppler ultrasound and five categories of non-invasive results by type and severity of PAD were defined. Legs with previous intervention (Rx), surgery or angioplasty, were evaluated separately. Claudication was reported in 42% of no Rx legs and 50% of Rx legs; 40% of claudication was atypical (not Rose); 64% of no Rx and 81% of Rx legs had PAD by non-invasive testing, and 27% of affected legs had severe PAD. The correlation between the severity of symptoms and the severity of ipsilateral PAD in no Rx legs was r=−0.40, p< 0.001. In Rx legs, this correlation was somewhat less (r=0.27, p< 0.001) due to more symptomatology at lesser degrees of PAD, suggesting reporting bias and/or more residual disease than evident from non-invasive testing. To our knowledge, these results provide the first comparison between a standardized assessment of leg pain and the severity of ipsilateral PAD by non-invasive testing.

Episodic memory changes are associated with the APOE- epsilon 4 allele in nondemented older adults

Objective: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE- epsilon 4). Background: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE- epsilon 4 allele. Methods: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n equals 17) or absence (n equals 35) of one or two APOE- epsilon 4 alleles. Results: APOE- epsilon 4 and non- epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE- epsilon 4 subjects demonstrated significantly poorer mean performances than non- epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 less than p less than 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE- epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non- epsilon 4 subjects who received follow-up demonstrated any cognitive decline. Conclusions: Results suggest that episodic memory changes in older adults are associated with APOE- epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT. NEUROLOGY 1995;45: 2203-2206

Effect of Light Treatment on Sleep and Circadian Rhythms in Demented Nursing Home Patients

OBJECTIVES To determine whether fragmented sleep in nursing home patients would improve with increased exposure to bright light. DESIGN Randomized controlled trial. SETTING Two San Diego-area nursing homes. PARTICIPANTS Seventy-seven (58 women, 19 men) nursing home residents participated. Mean age +/- standard deviation was 85.7 +/- 7.3 (range 60-100) and mean Mini-Mental State Examination was 12.8 +/- 8.8 (range 0-30). INTERVENTIONS Participants were assigned to one of four treatments: evening bright light, morning bright light, daytime sleep restriction, or evening dim red light. MEASUREMENTS Improvement in nighttime sleep quality, daytime alertness, and circadian activity rhythm parameters. RESULTS There were no improvements in nighttime sleep or daytime alertness in any of the treatment groups. Morning bright light delayed the peak of the activity rhythm (acrophase) and increased the mean activity level (mesor). In addition, subjects in the morning bright light group had improved activity rhythmicity during the 10 days of treatment. CONCLUSION Increasing exposure to morning bright light delayed the acrophase of the activity rhythm and made the circadian rhythm more robust. These changes have the potential to be clinically beneficial because it may be easier to provide nursing care to patients whose circadian activity patterns are more socially acceptable.

Predictors of outcome following severe head trauma: follow-up data from the traumatic coma data bank

Outcome as a function of employment status or return to school was evaluated in severely head-injured patients. A priori we selected the most salient demographic, physiological, neuropsychological and psychosocial outcome predictors with the aim of identifying which of there variables captured at baseline or 6 months would best predict employability at 6 or 12 months. Based on the patients evaluated at 6 months, 18% of former workers had returned to gainful employment and 62% of former students had returned to school. For those not back to work or school at 6 months, 31% of the former workers and 66% of the former students had returned by 12 months. Age, length of coma, speed for both attending and motor movements, spatial integration, and intact vocabulary were all significantly related to returning to work or school. The three most potent predictors for returning to work or school were intactness of the patients verbal intellectual power, speed of information processing and age.

Determinants of head injury mortality: importance of the low risk patient.

Data were obtained prospectively for 7,912 head-injured patients admitted from 1980 to 1981 to 41 hospitals in 3 U.S. metropolitan areas. Highly significant independent predictors of mortality were motor score, number of reactive eyes, systolic blood pressure, abdominal injury, chest injury, age, and hospital unit (hospital or group of hospitals). The difference between the number of deaths observed and the number expected, by hospital unit, ranged from 43% below expectation to 52% above expectation. The 2 hospital units with the lowest mortality had only 1 death, where 9.4 would be expected, in patients whose risk of death was estimated to be less than 10%. In the single hospital with clearly excess mortality, however, the standardized mortality ratios were 208, 135, and 144% for the risk groups whose probabilities of death were 0 to 50, 50 to 80, and 80 to 100%, respectively. The lack of deaths in those hospitals with the best mortality experience and the excess mortality in the hospital with the worst mortality experience appear to be explained largely by differences in patients who, by clinical criteria, seem to be at low risk for death, and not by severely injured patients.