Mark J. Alberts

Association of apolipoprotein E allele ∈4 with late-onset familial and sporadic Alzheimer's disease

Apolipoprotein E, type ϵ4 allele (APOE ϵ4), is associated with late-onset familial Alzheimers disease (AD). There is high avidity and specific binding of amyloid β-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE ϵ4 is significantly associated with a series of probable sporadic AD patients (0.36 ± 0.042, AD, versus 0.16 ± 0.027, controls [allele frequency estimate ± standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre dEtude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE ϵ4 allele (0.40 ± 0.026, p ≤ 0.00001). These data support the involvement of ApoE ϵ4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of β-peptide, and APOE ϵ4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

Hypothesis: Microtubule Instability and Paired Helical Filament Formation in the Alzheimer Disease Brain Are Related to Apolipoprotein E Genotype

A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-epsilon 3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filaments (PHFs); apoE4 does not bind tau. Tau promotes microtubule assembly and stabilizes microtubules; hyperphosphorylated tau does not bind, thereby destabilizing microtubules. Hyperphosphorylated tau may self-assemble into PHFs. Over time a bias toward destabilization of microtubules and the formation of neurofibrillary tangles may occur in individuals who inherit APOE4 alleles, leading to a shorter functional neuronal life span. This hypothesis focuses attention on two important aspects of AD research design: (1) Although the inheritance of APOE4 is associated with increased risk and decreased age of onset, apoE4 does not directly cause the disease. Our data point to the absence of an important function of apoE3 or apoE2 in individuals who do not inherit these alleles as the genetically relevant metabolic factor. This has important implications for design of experiments directed toward understanding the relevant neuronal metabolism. (2) Should this hypothesis be proven and confirmed, targets for pharmaceutical therapy designed to mimic the metabolic function of apoE3 or apoE2 become a realistic preventive strategy.

APOE genotype as a risk factor for ischemic cerebrovascular disease: A meta-analysis

Objective: To determine whether a specific apolipoprotein E (APOE) polymorphism is a risk factor for ischemic cerebrovascular disease (CVD; stroke or TIA). Background: The APOE ε4 allele is overrepresented in AD, atherosclerosis, and ischemic heart disease. In addition, ε4 carriers have higher plasma cholesterol levels than non-ε4 carriers. Methods: Using Medline (OVID and PubMed), a search was performed for all studies that examined APOE in ischemic CVD. The authors identified nine case–control studies that were suitable for analysis. Results: There were 926 patients with ischemic stroke or TIAs and 890 age- and sex-matched control subjects. Overall analysis revealed a significantly higher APOE-ε4 allelic frequency in affected patients compared with control subjects (0.14 versus 0.09; odds ratio, 1.68; 95% CI, 1.36 to 2.09; p < 0.001 ). There was a significant excess of the ε3 allele (0.85 versus 0.80) but not the ε2 allele (0.06 versus 0.06) in the control subjects compared with the ischemic CVD patients. Seven studies had data on APOE genotypes. Carriers of ε4 were more frequent among ischemic CVD patients than control subjects (27% versus 18%; odds ratio, 1.73; 95% CI, 1.34 to 2.23; p < 0.001). Conclusions: The APOE-ε4 allele and carriers of ε4 are more frequent among patients with ischemic CVD compared with control subjects. The ε2 allele does not appear to be protective for ischemic CVD. These findings imply a role for the APOE genotype in the pathogenesis of some cases of ischemic CVD.

Effects of public and professional education on reducing the delay in presentation and referral of stroke patients.

Background and Purpose Several emerging stroke therapies require patients to be treated within several hours of symptom onset. Past studies have documented a significant delay between symptom onset and hospital presentation. As part of an experimental treatment study using tissue-type plasminogen activator, we began a multifaceted program of public and professional education to reduce the delay in presentation and referral of acute stroke patients. Methods The educational efforts focused on improving the recognition of stroke symptoms, the study enrollment criteria, and the need for rapid treatment of stroke patients. This program included 1) interviews on television and radio, 2) newspaper articles, 3) lectures to local and regional primary care and emergency department physicians, 4) mailings to several thousand local physicians, 5) having neurologists on-call for referrals 24 hrs/day, and 6) use of the Duke Life-Flight helicopter. Results Since starting our program, 139 of 159 (86%) patients with cerebral infarction presented primarily to or were referred to our facility within 24 hours of symptom onset, compared with 70 of 187 37%) before our educational efforts (p < 0.00001). No significant change was seen in patients with intracerebral hemorrhage (23 of 30 [77%] within 24 hours after program, compared with 25 of 40 [63%] before educational efforts; p = 0.30). Conclusions These findings suggest that educational efforts aimed at the public and health professionals may increase recognition of stroke symptoms and reduce the delay in presentation and referral of stroke patients.

Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease

BACKGROUNDnWe aimed to determine the specificity, sensitivity, and predictive value of apolipoprotein E (APOE) genotyping in 67 consecutive patients with clinical diagnoses of sporadic Alzheimers disease (AD) who underwent necropsy.nnnMETHODSnWe studied patients who attended the Duke Memory Disorders Clinic and were diagnosed as having probable AD. These patients were followed up until they died. APOE genotyping was done during life in most cases, but in some brain tissue obtained at necropsy was used. Members of known AD families were excluded.nnnFINDINGSnAfter neuropathological examination 57 (85%) of 67 of our patients were confirmed as having AD including all 43 who had at least one APOE-epsilon 4 allele. None of the patients found not to have AD carried an epsilon 4 allele. In this series, the specificity of the epsilon 4 allele was 100%, the sensitivity 75%, the positive predictive value 100%, and the negative predictive value 42%. In this necropsy-confirmed series, the epsilon 4/epsilon 4 genotype predicted AD with 100% accuracy. The epsilon 3/epsilon 4 and epsilon 2/epsilon 4 genotypes were also unexpectedly highly specific for AD.nnnINTERPRETATIONnData from hundreds of necropsy-confirmed non-AD patients in other longitudinal necropsy series will allow the predictive value of APOE genotypes to be assessed with useful confidence limits.

Genetic linkage studies in Alzheimer's disease families

Alzheimers disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimers disease to chromosome 21 in a series of early onset AD families (mean age of onset less than 60). Familial late onset AD (mean age of onset greater than 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimers disease family members were identified and sampled. Ten of these families were of the late onset Alzheimers disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimers disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimers disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimers disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimers disease and indicate the need for continued screening of the genome in familial Alzheimers disease families.

Aspiration after stroke: Lesion analysis by brain MRI

Aspiration is a common problem following stroke, resulting in feeding difficulties and aspiration pneumonia. Despite past studies using clinical assessment and computed tomographic (CT) scans of the head, the correlation of stroke location with aspiration remains unclear. Since brain magnetic resonance imaging is more sensitive than CT for many stroke types, we have correlated MRI lesions with aspiration in patients who have sustained a stroke. We selected patients with acute stroke who underwent brain MRI and a swallowing evaluation. Aspiration was present in 21 of 38 patients (55%). Patients with just small vessel infarcts had a significantly lower occurrence of aspiration (3 of 14, 21%) compared to those with both large-and small-vessel infarcts (15 of 20, 75%, p=0.002). Multivariate analysis of several specific brain areas failed to identify a significant association between stroke location and the occurrence of aspiration. These findings suggest that patients who have experienced stroke should be individually evaluated for swallowing dysfunction regardless of stroke location or size, since even small-vessel strokes can be associated with aspiration in >20% of cases.

Swallowing in Alzheimer's disease

SummaryUsing a prospective case series design, we examined the incidence of oropharyngeal swallowing abnormalities in 25 patients with moderate or severe Alzheimers disease by videofluoroscopy. Aspiration occurred in 6 of 25 (28.6%). Only four patients showed unequivocally normal performance. Exploratory statistical analyses showed that swallowing abnormalities associated significantly with duration of dementia, eating dependency, and abnormal oral praxis. We observed a trend toward a higher incidence of aspiration in patients with more severe dementia. We conclude that oropharyngeal swallowing abnormalities, including aspiration, are more prevalent in patients with Alzheimers disease than in normal elderly individuals.

Acute hemodynamic changes during carotid artery stenting

To determine the clinical significance of acute hemodynamic disturbances during stenting in the carotid sinus region, we assessed the relation between intraprocedural changes in heart rate (HR) and blood pressure (BP) and adverse neurologic and cardiac outcomes. Eighteen patients underwent carotid stenting with the Wallstent (Schneider Inc). Suitable candidates had at least 60% diameter stenosis of the carotid artery by angiography. Initial and nadir HR and BP were recorded during the predilatation, stent delivery, and postdilatation periods. Bradycardia was defined as HR < or =60 beats/min and hypotension as systolic BP < or =100 mm Hg. Nineteen Wallstents were successfully deployed in all 19 carotid arteries. Some degree of bradycardia or hypotension occurred in 68% of carotid stent procedures, but administration of vasoactive medications was necessary in only 7 patients (37%) with more persistent hemodynamic disturbances. Hypotension or the need for continuous vasopressor therapy was significantly more common during postdilatation (32%) than in the predilatation period (5%) (p = 0.02). Bradycardia was not reduced by prophylactic atropine. In 1 patient the hemodynamic response to stenting may have contributed to an adverse neurologic and cardiac outcome. Thus, despite frequent fluctuations in HR and BP, most carotid stenting procedures were performed with excellent overall results, even in patients at high risk.

tPA in acute ischemic stroke United States experience and issues for the future

The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke.