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Biomedical subjects

W A Kukull

Publications and source records attributed to W A Kukull.

At least 55 records · Page 3Linked to original sources
PubMed1994

Symptom patterns and comorbidity in the early stages of Alzheimer's disease.

OBJECTIVE: To learn whether patients with early Alzheimer's disease tend to under-report or over-report symptoms and to compare their comorbidity with non-demented patients. DESIGN: Case Control Study in a population-based dementia registry. SETTING AND PATIENTS: Three groups of subjects (mean age 76) were enrolled from an HMO base population: 154 cases had clinically diagnosed probable Alzheimer's disease, 92 subjects were found to be not demented although they had complaints of cognitive impairment, and another 129 cognitively intact controls were enrolled after frequency-matching for age and sex. MEASUREMENTS AND RESULTS: Medical records were examined for the 2 years prior to enrollment. Symptoms suggestive of cognitive impairment were evident 7.8 months prior to enrollment (median 6 months) in 95% of cases, in 77% of the not demented subjects, and in 6% of controls. After corrections for multiple comparisons, only symptoms of cognitive impairment were more frequent in cases, whereas several common symptoms not suggestive of cognitive impairment (eg, gastrointestinal discomfort, joint pain, vision problems) occurred more often in controls and the not demented group, even though comorbidity was similar among all three groups (Charlson Index mean scores: case = 0.7, not demented = 0.7, control = 0.5). CONCLUSIONS: Persons with Alzheimer's disease do complain of symptoms clearly related to cognitive impairment early in the course of illness, but may under-report common symptoms not suggestive of cognitive impairment, even though their comorbidity is similar to patients without dementia.

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PubMed1994

Causes of death associated with Alzheimer disease: variation by level of cognitive impairment before death.

OBJECTIVE: To describe causes of death for patients with Alzheimer disease (AD) and other dementing illnesses enrolled in a population-based Alzheimer disease patient registry (ADPR) and to describe the variation in causes by the level of cognitive impairment before death in probable AD cases. SETTING: The ADPR enrolls and diagnoses newly recognized potential dementia cases occurring in a large, stable health maintenance organization. To date, 654 cases have been enrolled and followed annually to monitor cognitive decline and verify initial diagnosis. DESIGN: Longitudinal descriptive study. PATIENTS: ADPR enrollees who have died. MEASUREMENTS: Death certificates were obtained for all who died (total n = 104, probable AD = 55); reported causes of death were reviewed by a physician to determine the underlying cause. AD patients were categorized according to their Mini-Mental State Exam score (cognitive impairment) within 12 months of death as (a) mildly (21+), (b) moderately (15-20), or (c) severely (0-14) impaired, and underlying cause and all reported causes of death for each group were tabulated. MAIN RESULTS: Among probable AD patients, pneumonia and AD were most often recorded on death certificates when cognitive impairment within the year prior to death had reached the severe level; heart disease, stroke, and other common causes of death predominated in AD patients who were less cognitively impaired. CONCLUSIONS: When AD cases were followed from first diagnosis to death, the causes of death varied by level of cognitive impairment. Illnesses potentially amenable to treatment caused death at all levels of disease, but more so early in the course of AD. Cognitive impairment may make patients less able to recognize and report symptoms of medical problems, thereby complicating efforts to intervene.

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PubMed1994

The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease.

The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset < 60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele epsilon 4 and FAD in late-onset families; the epsilon 4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the epsilon 4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant (standard normal deviate [ZSND]) = 7.37, P < 10(-9); and ZSND = 4.07, P < .00005, respectively). No association between the epsilon 4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between epsilon 4 and AD was also observed in a group of unrelated subjects; the epsilon 4 frequency was .26 in affected subjects, versus .19 in controls (ZSND = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained (model 1, maximum Z[Zmax] = 0.61, recombination fraction [theta] = .30; model 2, Zmax = 0.47, theta = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Zmax = 2.02, theta = .15; model 2, Zmax = 3.42, theta = .05) or allele frequencies from the families (model 1, Zmax = 1.43, theta = .15; model 2, Zmax = 1.70, theta = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Zmax = 3.17, theta = .23; model 3, Zmax = 1.85, theta = .20). For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree-member analysis gave significant results for the late-onset kindreds, for ApoE (ZSND = 3.003, P = .003) and ApoCII (ZSND = 2.319, P = .016), when control allele frequencies were used but not when allele frequencies were derived from the families.

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PubMed1993

Conjugal Alzheimer's disease: is there an increased risk in offspring?

Thirty-one couples in which both spouses had the clinical diagnosis of Alzheimer's disease (AD) (confirmed by autopsy in 12) were ascertained. The mean age of onset of dementia was 75.1 +/- 7.4 years. These couples had 87 children, 63 still living. Seventeen (19.5%) of the children developed dementia, with a mean age of onset of 68.9 +/- 8.3 years. Thirty of the children of the conjugal AD couples survived to age 65 or longer and 14 (47%) of them developed dementia. This prevalence of dementia in the children of affected couples is much greater than that in the children of two control groups consisting of 234 couples in which one spouse had AD and 192 couples in which neither spouse was demented. Twenty-one of the conjugal AD couples had a family history of AD but the prevalence of dementia in their children was not greater than that in the children of conjugal AD couples without a family history of AD. These results represent additional evidence of an important genetic component in late-onset AD and provide empirical risk data for the children of conjugal AD couples.

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PubMed1993

Relationship between cigarette smoking and Alzheimer's disease in a population-based case-control study.

We investigated whether cigarette smoking is negatively associated with Alzheimer's disease (AD) in a population-based, frequency-matched, case-control study of 152 AD patients and 180 controls. Ever having smoked was associated with lower risk of AD (adjusted odds ratio = 0.61; 95% confidence interval: 0.37-0.99). Additional multivariate analyses demonstrated that education and history of hypertension modified this association. The direction of the modification was for higher education level and history of hypertension to further reduce the risk. The "dose-response" pattern showed the greatest risk reduction among those who smoked least and suggests a biologic mechanism of a dose-dependent up-regulation of nicotinic (cholinergic) brain receptors. These data, although consistent with current opinion about pathophysiology of AD, do not suggest smoking should be used as a preventive strategy for AD.

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PubMed1992

Cognitive impairment: dementia and Alzheimer's disease.

The importance of dementia, a syndrome of global cognitive impairment, has gained widespread recognition in the past two decades. The most common cause, Alzheimer's disease, may be the single greatest source of dysfunction among persons over age 85. The disease, distinct from normal aging, is progressive, has a highly variable course, and can have tremendous impact on families. Duration of symptoms averages eight to ten years from onset, four to five years from diagnosis. Diagnosis is often delayed, because of the insidious nature of the illness. Prevalence and incidence rates may vary severalfold between different studies. One consistent finding is the dramatic increase with age; prevalence rates are 25-48% for persons over age 85. The two most consistent risk factors for AD are age and positive family history. Another likely risk factor is head trauma. Alzheimer's disease is almost certainly due to heterogeneous causes. Biologic understanding of AD is primarily based on study of distinctive pathologic changes in the brain. Increasingly well-characterized pathologic changes precede the clinical manifestation of disease. Ultimately, the pathologic cause of AD is loss of neurons and neuronal connections in the brain, especially in the frontal and parietal association neocortex. Many systems are involved, but the most affected system is the cholinergic system, followed by the noradrenergic and serotonergic neurotransmitter systems. Drug treatment and other intervention strategies to prevent or delay progression of the disease have been limited, primarily because so little is known about the cause or risk factors for the disease. Current palliative treatments are attempts to minimize the morbidity of abnormal behaviors and medical complications associated with dementia. Ideally, treatment would either involve replacement therapy or drugs, which prevent or delay the pathologic changes that occur in AD. Two of the more promising experimental therapeutic attempts involve interruption of the pathogenetic events involving beta-amyloid and its precursor proteins and administration of NGF. Public health attempts at risk factor reduction are clearly premature. The next decade or two will likely witness improved understanding of the pathogenesis of Alzheimer's disease. Epidemiologic study will contribute to our knowledge of pathogenesis and may reveal heretofore unrecognized and, hopefully, modifiable risk factors. Social and clinical strategies to deal with a disease of such immense importance also needs development and evaluation. The public's interest in this disease is intense, and it looks to the scientific community for progress in understanding and managing this often tragic illness.

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PubMed1992

Increased platelet membrane fluidity as a diagnostic marker for Alzheimer's disease: a test in population-based cases and controls.

To test whether increased platelet membrane fluidity as measured by decreased steady state fluorescence anisotropy (rs) of diphenylhexatriene is a biologic/diagnostic marker for Alzheimer's disease (AD), we enrolled 95 clinically diagnosed, probable AD cases from our Alzheimer's Disease Patient Registry and 133 control subjects of similar age and sex randomly selected from the same population base as the cases. We measured rs in platelet membranes following published assay procedures. Laboratory personnel and investigators were blind to the identity of the samples; cases and controls were assayed in random order. Our analyses showed that the distributions of rs values were unimodal and similar for cases and controls. The overall mean differences (control mean-case mean) for the two established assay methods tested were 0.0011 and 0.0003. A nonparametric Wilcoxon rank sum test also showed no difference between cases and controls. Multivariate analysis adjusted for the significant effects of the processing date and analysis platelet recovery led to a final model with the adjusted mean difference of 0.0007 for the principal method. Increased platelet membrane fluidity is not an antemortem diagnostic or biologic marker for AD in our population.

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PubMed1991

Are there clinical and epidemiological differences between familial and non-familial Alzheimer's disease?

To determine whether there are clinical and epidemiological differences between familial and non-familial Alzheimer's disease, we studied 151 patients with the clinical diagnosis of Dementia of the Alzheimer Type (DAT). Eighty-four index patients (56%) had at least one relative with reported DAT-type memory loss; the remaining 67 did not. For comparison, patients with a positive family history were grouped into a suspected familial DAT (FDAT), and those with a negative family history were grouped into a suspected non-familial DAT (NFDAT). There were no significant differences between FDAT and NFDAT patients with respect to age of symptom onset, survival time, rate of cognitive decline, motor function, behavioral signs or symptoms, head trauma, thyroid dysfunction, maternal age, or birth order. There were no significant differences between pedigrees of FDAT and NFDAT patients in respect to the prevalence of Down's syndrome or age of mortality. To examine a more "familial" set of FDAT patients, an FDAT subgroup (F2DAT) consisting of 33 index patients with two or more affected relatives with DAT-type memory loss was compared to the 67 NFDAT patients in a similar analysis. No significant differences were found. However, NFDAT index patients had a higher reported prevalence of head trauma than those patients in the F2DAT subgroup (NFDAT 22%, F2DAT 7%, OR = 4.2, CI = 0.9-20.0, P = 0.08). Thus severe head trauma may be a more important etiological factor in the non-familial form of DAT. To better examine this tendency, future studies should be conducted utilizing a larger number of pedigrees and familial criteria which account for the number of persons at risk and the age at onset of disease.

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PubMed1991

APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease.

The amyloid precursor protein (APP) gene codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 "sporadic" AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis-Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD.

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PubMed1990

Interrater reliability of Alzheimer's disease diagnosis.

To determine interrater reliability of dementia diagnosis, 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients, based on a standardized set of medical record information. All patients had undergone similar examinations and follow-up to establish the initial clinical diagnosis (76% had autopsy). Raters were blind to the diagnosis and to follow-up information after the initial evaluation period. This paper presents interrater agreement (kappa values) for a diagnosis of Alzheimer's disease using the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for the clinical diagnosis of Alzheimer's disease, and the Eisdorfer and Cohen Research Diagnostic Criteria (ECRDC) for primary neuronal degeneration. The NINCDS showed somewhat higher average interrater reliability (kappa = 0.64) than the DSM-III (kappa = 0.55) and considerably higher interrater reliability than the ECRDC (kappa = 0.37). One rater displayed conspicuously lower levels of interrater reliability than the other 3, especially in DSM-III and ECRDC. This study indicates that interrater reliability of DSM-III and NINCDS criteria are comparable. Documentation of interrater reliability and, if necessary, training to improve reliability is an important consideration in research where different observers are diagnosing dementing illnesses.

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PubMed1990

The validity of 3 clinical diagnostic criteria for Alzheimer's disease.

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.

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PubMed1989

Distinguishing Alzheimer's disease from other dementias. Questionnaire responses of close relatives and autopsy results.

Epidemiologic study of Alzheimer's disease by family history requires that Alzheimer's be distinguished from other dementias. Identification of demented family members is usually based on recall by relatives. This study examines the validity of the classification of Alzheimer's disease and other dementias based on relatives' reports. Close relatives of autopsy-confirmed dementia cases were asked to complete a questionnaire describing the patient's symptoms. These informants were familiar with the patient's disease and involved in his/her care prior to death. The questionnaire included the DSM-III criteria for Primary Degenerative Dementia and the Hachinski Ischemic Scale. A diagnosis derived from the close relatives' responses was compared to the neuropathologic diagnosis for thirty-six cases: 20 Alzheimer's disease, 9 mixed Alzheimer's disease, and 7 non-Alzheimer's disease dementias. The diagnosis of Primary Degenerative Dementia derived from questionnaire responses had a sensitivity of 0.93 and specificity of 0.43 for pathologic Alzheimer's disease. Few vascular dementias were included in the series, thereby precluding the study of so-called multi-infarct dementia. Hachinski scores based on relatives' responses classified 40% of pathologically pure Alzheimer's disease cases as multi-infarct dementia (HIS greater than 7). Thus, using these elevated Hachinski scores to rule out Alzheimer's disease would cause substantial misclassification. Diagnosis based on questionnaire Primary Degenerative Dementia criteria was quite sensitive but relatively nonspecific. When attempting to obtain a complete family history or pedigree that describes the occurrence of Alzheimer's disease and other dementias in all family members, the questionnaire approach should be supplemented with additional information from medical records, physicians, and other relatives.

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PubMed1987

Adverse drug reactions associated with global cognitive impairment in elderly persons.

Adverse drug reactions causing cognitive impairment are an important problem in the elderly. Thirty-five patients with adverse drug reaction were identified among more than 300 patients evaluated for cognitive impairment and compared with patients without adverse drug reaction. Sedative hypnotic agents, especially long-acting benzodiazepines, were the commonest drugs associated with cognitive impairment in this population. The number of drugs used, use of sedative hypnotics and antihypertensives, and falling were strongly associated with adverse reactions in logistic regression analyses. The relative odds of an adverse reaction associated with cognitive impairment increased as the number of prescription drugs increased, exceeding 9.0 for patients taking four or more prescription drugs. Adverse drug reactions are an important source of excess morbidity in patients with dementia or suspected dementia. Strategies that could minimize this problem include a high index of suspicion, drug-free trials in suspected cases, and careful monitoring of drug therapy.

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PubMed1986

Rapid estimation of hospitalization charges from a brief medical record review. Evaluation of a multivariate prediction model.

In settings where an itemized hospital bill is not generated, estimation of hospitalization charges for research or administrative purposes can be a laborious task. This article examines the extent to which the number of hospital days spent outside an intensive care unit (ICU), number of days in an ICU, number of laboratory tests performed, number of x-rays, and number of surgeries can be used in a multiple regression equation to impute inpatient charges for a sample of 103 hospitalizations at a Veterans Administration hospital. These predictor variables, all of which are readily ascertained in a brief medical record review, accounted for about 97% of the variance in imputed hospital charges. The bootstrap method was applied for validation of the prediction equation. Application of the method described here may be of value to researchers concerned with hospital charge estimation in non-fee-for-service settings.

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PubMed1986

Symptomatic depression in elderly medical outpatients. I. Prevalence, demography, and health service utilization.

The authors assessed the prevalence and demography of depressive symptoms, their association with specific chronic diseases, and their influence on health service use in a large sample of elderly men seen in a primary care setting. Twenty-four percent of respondents reported clinically significant depressive symptoms; the prevalence of major depressive disorders was estimated at 10%, but only 1% reported receiving mental health treatment by a specialist. Self-reported marital separation or divorce and physical disability affecting employment were strongly associated with high depression scores, whereas the normative stresses of aging (widowhood, retirement, social isolation) were not. Only chronic lung disease was differentially associated with high depression scores, and this effect was weak. The authors discuss the implications of these findings for the design of comprehensive health services for the elderly with chronic disease.

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PubMed1984

Rapid eye movement sleep measures of Alzheimer's-type dementia patients and optimally healthy aged individuals.

It has been suggested that rapid eye movement (REM) sleep measures may be useful in the differential diagnosis of affective disorders. To determine what changes, if any, of REM measures occur in Alzheimer's dementia we examined the REM sleep of nine control and nine mild, nine moderate, and nine severe dementia subjects with probable Alzheimer's disease (AD). Control and mild and moderate AD groups were screened to exclude major depression. REM latency, REM time, REM activity, and REM density were examined. Results indicated that REM sleep measures are minimally affected by mild dementia. None of the REM sleep variables reported here successfully discriminated mild AD subjects from controls. However, REM time and REM latency were significantly affected in later stages of dementia. Total time in REM and REM latency successfully classified control and moderate-severe AD patients. In addition, the pattern of REM density across the night was also affected by severity of dementia. The results of this study, when compared to published REM measure findings in major depression, indicate that with proper cautions REM sleep measures may prove useful in the differential diagnosis of dementia and depression in geriatric patient populations.

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