Biomedical subjects

W Kukull

Publications and source records attributed to W Kukull.

9 recordsLinked to original sources

PubMed2005

The North American Multiple System Atrophy Study Group.

The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Animals↗

PubMed1999

The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series.

CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Aged↗

PubMed1999

Clinico-neuropathological correlation of Alzheimer's disease in a community-based case series.

OBJECTIVES: Most clinico-neuropathological correlative studies of Alzheimer's Disease (AD) are based on research cohorts that are not necessarily generalizable to patients seen in the general medical community. In this study, we examine the accuracy of the criteria used in diagnosing AD in a community-based case series of patients with memory complaints. DESIGN AND PARTICIPANTS: Clinical and neuropathological diagnoses were obtained from 134 patients evaluated for dementia who subsequently underwent autopsy. SETTING: Subjects who exhibited new symptoms of dementia and were enrolled in the University of Washington/Group Health Cooperative Alzheimer's Disease Patient Registry were eligible for this study. MEASUREMENTS: Clinico-pathological correlation was performed using NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria. RESULTS: Ninety-five of the 134 cases studied met CERAD neuropathological criteria for AD. The sensitivity of NINCDS-ADRDA "probable AD" was 83% (diagnosing AD correctly) and overall clinical diagnostic accuracy was 75%. However, there was a high rate of additional neuropathological findings. Only 34 of the 94 cases had pure AD on neuropathology, whereas the remainder frequently had coexisting vascular or Parkinson's disease lesions. CONCLUSIONS: This study of a large series of community-based incident dementia cases provides a way of judging the adequacy of currently available clinical diagnostic criteria. It also shows that co-existing neuropathological findings are common in community-based AD.

Aged↗

PubMed1997

Progression to dementia in patients with isolated memory loss.

BACKGROUND: The diagnosis of dementia requires both memory loss and at least one other type of cognitive impairment. The natural history of patients with severe memory loss but no other type of cognitive impairment is poorly understood. We studied progression to dementia in patients with isolated memory loss. METHODS: From a registry of 811 patients with cognitive complaints, 21 patients with severe isolated memory loss of unknown cause were identified and followed up for a mean of 48 months. A comparison group of 198 patients on the same register was identified with newly recognised cognitive complaints but without dementia or isolated memory loss (mean follow-up 31 months). We did a range of neuropsychological tests at intake. FINDINGS: During follow-up, 48% (n = 10) of patients with isolated memory loss-developed dementia compared with 18% (n = 36) of the comparison group. Life-table analysis showed the mean times to a diagnosis of dementia was 3.77 years (95% CI 2.99-4.56) and 5.96 years (5.60-6.31), respectively (p = 0.01). The neuropsychological tests did not predict which patients would progress to dementia. INTERPRETATION: Patients with severe isolated memory loss have an increased risk of developing dementia and should be closely followed-up.

Adult↗

PubMed1996

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Alzheimer Disease↗

PubMed1996

Impact of sample selection on APOE epsilon 4 allele frequency: a comparison of two Alzheimer's disease samples.

OBJECTIVE: In a highly selected sample of unrelated Alzheimer's disease (AD) patients, we found that the APOE epsilon 4 allele frequency was higher than previously reported. Differing selection and ascertainment criteria may lead to these differences. To address this possibility, we compared the epsilon 4 allele frequency in two samples of AD patients selected from the same geographical area. SETTING AND PARTICIPANTS: Cases (n = 55) and controls (n = 99) from a research clinic-based sample were compared with subjects (n = 537) from a community-based AD patient sample. The samples consisted of unrelated cases who met NINCDS/ADRDA criteria for probable AD. DESIGN AND MEASUREMENTS: Clinical characteristics and APOE genotype data were obtained from AD cases and controls from both samples. RESULTS: Frequency of APOE epsilon 4 allele in the research cases compared with the community cases (0.45 vs 0.36) was nearly significant. We compared demographic and clinical characteristics that might account for this difference and found that the research cases were younger, had an earlier age of onset, and had more advanced disease than the community cases. After onset age was controlled, there was no overall difference between epsilon 4 allele frequency of the two samples. CONCLUSIONS: We found that the epsilon 4 allele frequency tended to be higher in the research AD sample compared the community-based sample. The two samples differed in several demographic and clinical characteristics. We conclude that research-based samples may lead to enrollment of younger patients with more severe disease who have higher APOE epsilon 4 allele load. This potential selection bias must be considered in the interpretation of studies of APOE allele frequency.

Age of Onset↗

PubMed1995

Geographically overlapping Alzheimer's disease registries: comparisons and implications.

In the medical and epidemiologic literature, a registry denotes a data base in which registrants share some common characteristic such as disease category. One criticism of registries is that they frequently collect subjects in a haphazard fashion and, hence, are "nonrepresentative of the population purportedly being represented." In this report, we compare two registries: an incident-based Alzheimer's Disease Patient Registry (ADPR) recruiting subjects for epidemiologic studies from a large health maintenance organization; and an Alzheimer's Disease Research Center (ADRC) registry recruiting subjects for phenomenologic, biologic, and pharmacologic studies. While these registries share personnel, overlap geographically, and use similar diagnostic procedures, they differ substantially in their missions and resulting recruitment strategies. We compared these registries with respect to demographic characteristics and cognitive features at subject entry. Subjects enrolled in the incident-based registry are older and report shorter time between symptom onset and recruitment. They are less demented and mirror the general population demographically more closely than do subjects in the other registry. The ADRC registry contains a much greater proportion of subjects with higher educational attainment.

Age Factors↗

PubMed1994

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part VI. Family history assessment: a multicenter study of first-degree relatives of Alzheimer's disease probands and nondemented spouse controls.

Although familial factors in Alzheimer's disease (AD) are well established, uniform family-history assessment in genetic and epidemiologic studies of AD is needed to reconcile the divergent estimates of the cumulative risk of this illness among relatives of AD probands. To answer the need, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a standardized Family History Assessment of AD to identify the presence of AD, Parkinson's disease (PD), and Down's syndrome (DS) in family members. This paper describes the use of this new assessment instrument in 118 patients with AD (estimated mean age at onset [+/- SD] = 64.5 +/- 7.7 years) and their nondemented spouses who were enrolled in 11 different CERAD sites in the U.S. The first-degree relatives of the probands with AD had a significantly greater cumulative risk (p < 0.005) of AD or primary progressive dementia (24.8%) than did the relatives of spouse controls (15.2%). Furthermore, the cumulative risk for this disorder among female relatives of probands was significantly greater than that among male relatives. There were no differences between the families of probands and controls for the numbers of affected first-degree relatives with PD or DS. This is the first reported multicenter family-history study of AD, and it supports earlier reports of familial factors in AD and indicates a higher risk to female relatives of AD probands. The CERAD Family History Assessment instrument may be useful for further multicenter and epidemiologic studies designed to delineate familial factors associated with AD.

Age of Onset↗

PubMed1989

On the uses of registries for Alzheimer disease.

Alzheimer disease (AD) is the most common dementing illness of the elderly; more than 2 million persons in the United States may be affected. Although funding levels for research into the causes, prevalence, possible risk factors for, and treatment of AD have increased rapidly in recent years, many basic issues remain unresolved. To address some of these issues, several states have passed legislation to develop registries for AD. This paper discusses the potential uses of such large-scale registries for AD and suggests alternative ways of gathering the information needed by researchers and public health officials. The key issues of purpose, case definition, and ascertainment are discussed in detail, and we note that the primary impediment to implementation of large-scale registries for AD at this time is the lack of a standardized, reliable, and valid diagnostic method. Three types of alternatives to registries are discussed, including use of current data, small-scale registries (such as a local hospital registry), and sampling studies.

Alzheimer Disease↗