The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer.

Small-cell lung cancer (SCLC), a chemotherapy-responsive disease, is characterized by neuroendocrine properties. In contrast, non-small-cell lung cancer (NSCLC) is at best moderately responsive to chemotherapy, and only 10% to 20% of cases demonstrate neuroendocrine properties. The present study is a retrospective analysis of the use of immunoperoxidase markers for neuron-specific enolase (NSE), Leu-7, and chromogranin A in NSCLC patients treated with chemotherapy. It was designed to determine if the presence of neuroendocrine markers predict for response to chemotherapy. The diagnostic slides and blocks were obtained on 52 NSCLC patients who were treated with chemotherapy (26 responders and 26 nonresponders). Immunoperoxidase studies were performed, and slides were scored without knowledge of the patient's response. Markers were positive in responders and nonresponders, respectively, as follows: NSE, 14 of 26 (54%) versus seven of 26 (27%), P = .04; Leu-7, 11 of 25 (44%) versus five of 26 (19%), P = .08; and chromogranin A, three of 26 (12%) versus 0 of 26 (0%), P = .71. Two markers were positive in 10 of 26 responders (38%) and 0 of 26 nonresponders (0%), P less than .01. Responders with two or more positive markers showed superior survival (median, 79 weeks) compared with responders with fewer than two positive markers (median, 51 weeks) and nonresponders (median, 27 weeks). These data suggest that the presence of neuroendocrine markers in NSCLC is associated with an increased likelihood of response to chemotherapy and may add to the standard parameters (performance status, weight loss) used to select patients for chemotherapy.

Rate of cognitive decline in Alzheimer's disease is associated with EEG alpha power.

Fifteen patients with Alzheimer's disease who were initially mildly or moderately impaired were followed for up to 4 years. Scores of the Mini-Mental State Examination (MMSE) were regressed on time of examination (measured at 6-month intervals) to estimate cognitive progression rates in individual patients. A quantitative electroencephalographic (EEG) examination was administered to each patient. Log-absolute EEG power in the alpha bandwidth (8-12 Hz) was found to be correlated with the computed rate of MMSE decline. This association was present for electrode sites across all regions of the scalp and remained significant when the effects of current cognitive severity were partialled out. These data suggest that a quantitative EEG measure (absolute alpha power) is related to the rate of cognitive decline in patients with Alzheimer's disease.

The Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease. The Behavioral Pathology Committee of the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: The purpose of the study was to develop a standardized instrument, the Behavior Rating Scale for Dementia, for rating psychopathology in patients with probable Alzheimer's disease and to conduct a multicenter pilot study of this instrument. METHOD: The rating scale was developed collaboratively on the basis of clinical experience and existing instruments. Items were scaled according to frequency of psychopathology and were administered to an informant who was familiar with the subject. The scale was administered in a standardized manner by trained examiners who had met predetermined certification standards. The study group consisted of 303 subjects with probable Alzheimer's disease who had undergone standardized clinical evaluations by the Consortium to Establish a Registry for Alzheimer's Disease. RESULTS: Subjects had an average of 15 problems rated as present in the preceding month. Wide variability in the nature of disturbances was found, with a number of items rated as present since the illness began but not in the past month. Interrater agreement was high. Factor analysis suggested eight preliminary factors that mapped onto clinically relevant domains: depressive features, psychotic features, defective self-regulation, irritability/agitation, vegetative features, apathy, aggression, and affective lability. CONCLUSIONS: The Behavior Rating Scale for Dementia provides a standardized, reliable measure that can be administered to caregivers of demented subjects. On the basis of the present study, the scale has been revised slightly. After additional studies in progress, the Behavior Rating Scale for Dementia will be available for general use in assessing a wide range of psychopathology in dementia.

Pathologic correlates of dementia in Parkinson's disease.

Histopathologic studies of the cerebral cortex, hippocampus, and three subcortical nuclei were performed in four patients with Parkinson's disease whose mental status had been evaluated by neuropsychologic testing. Clinicopathologic correlations suggest that dementia with marked visuospatial disturbance as well as severe aphasia may be associated with severe neuronal loss in subcortical nuclei, without significant numbers of plaques or tangles in the hippocampus and cerebral cortex. Furthermore, memory loss may not be consistently related to neuronal loss in the nucleus basalis of Meynert, particularly in non-Lewy body parkinsonism.

Predictors of cognitive and functional progression in patients with probable Alzheimer's disease.

We followed 65 patients with probable Alzheimer's disease, who were initially mildly to moderately impaired, with semiannual assessments of cognitive and functional performance for up to 4 years. Scores on the Mini Mental State Examination and a combination of instrumental and self-maintenance scale of activities of daily living were regressed on time of examination (measured in 6-month increments) to estimate cognitive and functional progression rates in individual patients. Lower scores on the verbal neuropsychological tests at the time of study entry, more aggressive behavior, and sleep disturbance during the first year of observation predicted faster cognitive progression. Faster functional progression was predicted by paranoid behavior, hallucinations and activity disturbances during the first year and the presence of extrapyramidal signs and lower scores on nonverbal neuropsychological tests at the time of entry into the study. Hallucinations occurred independently of cognitive severity and may identify a distinct subgroup of patients with rapid functional progression. Because of the greater significance of functional progression for caregivers' ability to manage patients, the presence of specific behavior problems early in the disease course may help to identify individuals who will experience greater functional decline and be at risk for earlier institutionalization.

Head injury as a risk factor for Alzheimer's disease.

A case-control study was performed in which the frequency of prior head injury was assessed in 78 patients with dementia of the Alzheimer type (DAT) and 124 control subjects matched for age, sex, and race. A history of head injury with loss of consciousness was reported in 25.6% of patients and 5.3% and 14.6% of hospital and neighborhood controls, respectively. Matched-pair analysis of patients and hospital controls yielded an odds ratio of 4.50, which was significant (p less than 0.01). The ranges of times of occurrence of head injuries were similar in patients and controls, spanning several decades. The findings suggest a possible etiologic role for head injury in DAT.

Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study.

OBJECTIVE: To determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. METHODS: Postmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. RESULTS: Hippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). CONCLUSION: Volumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.

Relationship of motor symptoms to intellectual deficits in Parkinson disease.

We studied 60 patients with idiopathic Parkinson disease with motor and neuropsychologic tests to ascertain whether the severity of motor symptoms was associated with the degree of neuropsychologic deficity. Significant correlations were found between the severity of brady kinesia and impaired performance on tests assessing visual-spatial reasoning and psychomotor speed. More severe tremor was associated with better performance on a spatial orientation memory test. There relationships remained when age, age at onset, and self-rated depression were controlled. The findings suggested that cognitive impairment may result from the same subcortical lesions that cause motor symptoms.

Head circumference and incident Alzheimer's disease: modification by apolipoprotein E.

BACKGROUND: The clinical expression of AD likely occurs when the accumulation of degeneration in specific brain regions leads to the descent below a critical threshold of "brain reserve" beyond which normal cognitive function cannot be maintained. The association between head circumference (HC), a measure of brain reserve, and the incidence of probable AD was examined in a large nondemented cohort that has been followed since 1992 and its modification by APOE epsilon 4 genotype. METHODS: Fifty-nine incident cases of probable AD were identified from 1,869 initially nondemented individuals seen at the baseline examination (1992 to 1994) and followed for a mean of 3.8 years. Variables measured at baseline included age, education, gender, HC, height, weight, and score on the National Adult Reading Test-Revised. APOE was genotyped at the time of the first biennial examination (1994 to 1996) and was available for 1,111 individuals in the cohort. Cox proportional hazard regression was performed to estimate hazard ratios (HR) for probable AD for HC and other covariates. RESULTS: Incident cases were significantly older, less educated, shorter, and lighter, had lower estimated verbal IQ scores, and were more likely to have at least one APOE epsilon 4 allele than unaffected individuals. The HR associated with the lowest tertile of HC (<21.4 inches) adjusted for education, gender, and APOE epsilon 4 was 2.3 (95% CI 0.7 to 6.9, p = 0.16). The HR for one or two APOE epsilon 4 alleles was significant (HR = 4.8, 95% CI 1.8 to 12.9, p = 0.002). The combination of low HC and APOE epsilon 4 strongly predicted earlier onset of AD with HR = 14.1 (95% CI 3.0 to 65, p = 0.0007). CONCLUSIONS: Smaller HC, in the presence of the APOE epsilon 4 allele, hastens the age at onset of AD. These results support the brain reserve hypothesis and its importance in precipitating the clinical expression of AD among genetically predisposed individuals.

Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging?

OBJECTIVES: To examine the relationship between APOE genotype and cognitive functioning in normal aging, and to determine whether this relationship was moderated by age or the presence of a number of disease conditions, including cardiovascular disease and diabetes. METHODS: The sample was drawn from the Charlotte County Healthy Aging Study, a community-based, cross-sectional study of randomly selected older adults in Charlotte County, FL. A total of 413 older adults (mean age = 72.90 years) were examined in the current study. Participants completed tasks that indexed a variety of dimensions of cognitive functioning, including episodic memory, implicit memory, psychomotor speed, and attention. In addition, participants provided self-reported and objective indices of health status and were genotyped for APOE. RESULTS: Mean-level results indicated that groups with and without the APOE-epsilon4 allele performed similarly on all domains of cognitive functioning. Significant age group differences were observed in episodic memory, psychomotor speed, and attention but not implicit memory. Significant gender differences were present for episodic memory and the Stroop test. Analyses also indicated that participants' age did not exert an impact on the relationship between APOE-epsilon4 and cognitive functioning. Further, the presence of cardiovascular disease or diabetes did little to moderate the relationship between APOE-epsilon4 and cognition. CONCLUSIONS: The authors found no evidence for a relationship between presence of the APOE-epsilon4 allele and cognitive functioning. Further, age or the presence of a number of chronic conditions did not significantly moderate the effect of APOE genotype on cognitive performance. These results indicate that the presence of the epsilon4 allele is not a risk factor for cognitive impairment in normal aging.

Use of twin cohorts for research in Alzheimer's disease.

The causes of Alzheimer's disease (AD) remain a mystery despite the recent identification of several putative environmental risk factors and the discovery of several linked genetic loci and point mutations associated with the disease. Particularly uncertain is the generalizability of the genetic findings to the common forms of disease encountered in clinical practice or population research. Twin studies of AD can illuminate causal mechanisms, both genetic and environmental. This consensus document explores the rationale for such twin studies, as well as a number of methodologic problems that render them difficult to implement or interpret. We review existing twin studies of AD and note several ambitious new studies. Finally, we delineate several practical strategies for the near future of twin research in AD.

Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A re-analysis of the data from 11 case-control studies was performed to investigate the association between head trauma and Alzheimer's disease (AD). To increase comparability of studies, exposures were limited to head trauma with loss of consciousness (hereafter referred to as 'head trauma') and comparisons were restricted to community (versus hospital) controls. Test for heterogeneity across studies was negative; consequently, data were pooled in subsequent analyses. The pooled relative risk for head trauma was 1.82 (95% confidence interval: 1.26-2.67). Stratified analyses showed stronger associations in cases without a positive family history of dementia and in males (versus females). Adjustment of the pooled relative risk for family history of dementia, education and alcohol consumption did not alter significantly the association between head trauma and AD. There was no interaction effect between head trauma and family history of dementia, suggesting that these risk factors operate independently. Mean age of onset was not significantly different in cases with a history of head trauma compared to cases without such a history. The findings of the pooled analysis support an association between reported head trauma and AD.

Medical history and the risk of Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

In a re-analysis of eight case-control studies on Alzheimer's disease we explored several medical conditions that had previously been suggested as possible risk factors for Alzheimer's disease. History of hypothyroidism was increased in cases as compared to controls (relative risk 2.3; 95% confidence interval 1.0-5.4). Severe headaches and migraine were inversely related to Alzheimer's disease (relative risk 0.7; 95% confidence interval 0.5-1.0). More cases than controls reported epilepsy before onset of Alzheimer's disease (relative risk 1.6; 95% confidence interval 0.7-3.5), especially for epilepsy with an onset within 10 years of onset of dementia. Neurotropic viruses, allergic conditions, general anaesthesia and blood transfusions were not associated with Alzheimer's disease.

Alcohol and tobacco consumption as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for alcohol consumption and cigarette smoking. Five studies included in the meta-analysis of alcohol consumption. Alcohol consumption was computed in terms of average weekly intake, measured in ounces of 'pure alcohol'. This variable was categorized into tertiles to represent low, medium and high intake. Analyses showed no excess estimated risk of Alzheimer's disease for any level of alcohol intake. Smoking was analysed in three different manners: (1) lifetime prevalence of smoking (ever/never)--this included eight studies; (2) amount smoked (less than or equal to one pack per day versus more than one pack per day)--this included seven studies; and (3) pack-years--including four studies. A statistically significant inverse association between smoking and Alzheimer's disease was observed at all levels of analysis, with a trend towards decreasing risk with increasing consumption (p(trend) = 0.0003). A propensity towards a stronger inverse relation was observed among patients with a positive family history of dementia, but the difference between this group and the group with no such history was not statistically significant. Although the observed disturbance in nicotinic receptor function in Alzheimer's disease may provide an explanation for these findings, possible biases related to the selection or survival of study subjects cannot be fully ruled out at this time. Prospective, community-based studies of incident cases of Alzheimer's disease are needed to document in detail the smoking history, age of onset of disease and survival of patients and cognitively intact people by smoking status.

Occupational exposures to solvents and lead as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for occupational exposures to solvents and lead. Three studies had data on occupational exposure to solvents. Among cases, 21.3% were reported to have been exposed; among controls, this figure was comparable (20.9%). This yielded a pooled matched relative risk of 0.76 (95% CI: 0.47-1.23). Four studies had data on exposure to lead. Exposure frequencies were 6.1% in cases and 8.3% in controls. This resulted in a pooled matched relative risk of 0.71 (95% CI: 0.36-1.41). The meta-analysis was particularly useful in validating negative results from individual studies and in increasing the statistical power for the analysis of lead exposure, where stratum-specific cell sizes were frequently smaller than five in individual studies. However, since exposure in the various studies was ascertained in a rather broad manner, prospective studies are recommended which focus on high-risk occupational populations and which determine the incidence of Alzheimer's disease in these and comparable unexposed populations.

Psychiatric history and related exposures as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group.

Data from case-control studies of Alzheimer's disease (AD) were pooled to examine the possible roles of history of depression, anti-depressant treatment and adverse life events as risk factors. History of depression was found to be associated with AD, although the effect was confined to late onset cases. The association held for episodes of depression more than 10 years before AD onset, as well as for episodes occurring within a decade of onset. No association was found with anti-depressant treatment. However, data were only available from two studies, limiting the power of the analysis. Also, no association was found with the three major life events considered in the pooled analysis: death of spouse, death of a child and divorce.

Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies.

Case-control studies of Alzheimer's disease were re-analysed to examine the association of Alzheimer's disease with family history in first degree relatives of dementia, Down's syndrome and Parkinson's disease. Overall, the relative risk of Alzheimer's disease for those with at least one first degree relative with dementia was 3.5 (95% confidence interval 2.6-4.6). Stratification according to age of onset of Alzheimer's disease showed that the relative risk decreased with increasing onset age. However, among patients with an onset of disease after 80 years, there were still significantly more subjects with one or more first degree relatives with dementia as compared to controls (relative risk 2.6; 95% confidence interval 1.3-5.2). The relative risk of Alzheimer's disease was significantly lower in patients who had one first degree relative with dementia (relative risk 2.6; 95% confidence interval 2.0-3.5) as compared to those who had two or more affected relatives (relative risk 7.5; 95% confidence interval 3.3-16.7). Furthermore, the re-analysis showed a significant association between Alzheimer's disease and family history of Down's syndrome (relative risk 2.7; 95% confidence interval 1.2-5.7), which was strongest in those patients who had a positive family history of dementia. The relative risk of Alzheimer's disease for those with a positive family history of Parkinson's disease was 2.4 (95% confidence interval 1.0-5.8).

Clean intermittent catheterization: safe, cost-effective bladder management for male residents of VA nursing homes.

OBJECTIVES: To compare the safety and cost of clean versus sterile intermittent bladder catheterization in male nursing home residents. To provide evidence to support the hypothesis that intermittent catheterization is a valid, alternative method of bladder management in male residents of long-term care in whom urinary retention is a documented problem. DESIGN: Randomized clinical trial. SETTING: Three long-term care sites having predominantly male populations. PARTICIPANTS: Eighty male veterans, residents of three long-term care facilities, ranging in age from 36 to 96 years with a mean age of 72. INTERVENTIONS: Standardized procedures for clean and sterile intermittent catheterization (IC) were implemented by staff nurses at each site. Patients were randomized into clean and sterile IC groups. Nursing time and catheterization equipment usage were recorded using bar code readers. Clinical data were collected from the medical chart. Treatment of urinary tract infection was prescribed by the medical personnel responsible for each individual resident. MEASUREMENTS: We compared the number of treatment episodes for symptomatic bacteriuria between groups randomized to receive either clean or sterile intermittent catheterization. Laboratory analysis of blood and urine was done on predetermined days. Control variables were research site and patient history of urinary tract infection within the last 6 months. A cost comparison of nursing time and equipment usage for the two catheterization techniques was also performed. RESULTS: No significant differences were found between clean and sterile groups with regard to number of treatment episodes, time to first infection, type of organism cultured, or cost of antibiotic treatment. The cost of sterile technique was considerably higher both in terms of nursing time and supplies. CONCLUSIONS: Findings from this study demonstrate that clean technique intermittent catheterization is a safe and cost-effective bladder management technique with male, nursing home residents, despite the frailty of this high risk population. An annual savings of approximately $1460 per patient in nursing time and catheterization supplies could be anticipated if a patient were catheterized an average of four times per day substituting clean IC technique for sterile IC technique.

Attitudes toward use of nursing homes and home care in older Japanese-Americans.

OBJECTIVE: A cohort of 1142 older Japanese Americans was identified to study preferences and attitudes regarding use of long-term care (nursing home or home care). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Older Japanese Americans in King County, Washington. RESULTS: Subjects were asked to consider hypothetical situations in which they were temporarily disabled by hip fracture or permanently disabled by dementing illness. If they fractured a hip, only 12% intended to use a nursing home; 29% intended to recover at home with the help of family or friends; another 54% intended to use paid home health care. If they became demented, the majority (53%) intended to use a nursing home; only 11% intended to rely on family or friends for care, and another 29% intended to use paid home health care. Similar responses were observed when subjects were asked what most members of their family or friends would wish them to do; however, they tended to value the perceived wishes of religious figures or the Japanese American community-at-large less than those of family or friends. Significant correlates with intention to enter nursing homes were lack of social support (unmarried, few or no close relatives or housemates), female gender, and high levels of acculturation into American society (never lived in Japan, English-speaking only). Other factors that were not significantly correlated were health perceptions, satisfaction and life control scales, and health care utilization (hospitalizations and MD visits). In multivariate logistic regression, marital status and level of acculturation were the most powerful independent predictors of intention to enter nursing homes. Age and female gender were predictors of intention to use home care. In the base population of subjects, the prevalence of nursing homes use (5%) was similar to that of the general US older population. CONCLUSIONS: We conclude that older Japanese Americans in the Pacific Northwest often intend to enter nursing homes if they became disabled by dementing illness. Actual use is similar to other older populations. This may be attributable largely to the existence of an ethically appropriate nursing home which is strongly supported by, and familiar to, this close-knit community. Intention to use long-term care services appears to be dependent primarily on the level of social supports and acculturation into American society.

Heritability for Alzheimer's disease: the study of dementia in Swedish twins.

BACKGROUND: Alzheimer's disease has been thought to have familial and sporadic forms, and several genetic defects have been identified that chiefly explain early-onset familial cases. In this study, our purpose was to detect all cases of dementia in an established twin registry and to estimate total extent of genetic contribution to liability to Alzheimer's disease. METHODS: At the first stage, members of the registry were screened for dementia, using in-person or telephone mental status testing. At the second stage, those who screened positively and their partners were referred for clinical work-ups, including neuropsychological assessment, physician examination, laboratory tests, and neuroimaging. Clinical diagnoses were assigned at a multidisciplinary consensus conference. Probandwise concordance rates were examined by zygosity, and structural modeling was applied to the data to estimate genetic and environmental influences, using both single- and multiple-threshold models. RESULTS: Sixty-five pairs were identified in which one or both was demented. The probandwise concordance rate for Alzheimer's disease among monozygotic pairs was 67%; the corresponding figure for dizygotic pairs was 22%. Heritability of liability to Alzheimer's disease was estimated to be .74; to any dementia, .43. The other variance is attributable to environmental influences. CONCLUSIONS: Findings indicate a substantial genetic effect for these predominantly late-onset Alzheimer's disease cases. At the same time, structural modeling results and large intra-pair differences in age of onset suggest that environmental factors are also important in determining whether and when an individual may develop dementia.