Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity.

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

Comparative reliability analysis of publicly available software packages for automatic intracranial volume estimation.

Intracranial volume is an important measure in brain research often used as a correction factor in inter subject studies. The current study investigates the resulting outcome in terms of the type of software used for automatically estimating ICV measure. Five groups of 70 subjects are considered, including adult controls (AC) (n=11), adult with dementia (AD) (n=11), pediatric controls (PC) (n=18) and two groups of pediatric epilepsy subjects (PE1.5 and PE3) (n=30) using 1.5 T and 3T scanners, respectively. Reference measurements were calculated for each subject by manually tracing intracranial cavity without sub-sampling. Four publicly available software packages (AFNI, Freesurfer, FSL, and SPM) were examined in their ability to automatically estimate ICV across the five groups. Linear regression analyses suggest that reference measurement discrepancy could be explained best by SPM [R(2)= 0.67;p <; 0.01] for the AC group, Freesurfer [R(2) = 0.46; p = 0.02] for the AD group, AFNI [R(2)=0.97;p<; 0.01] for the PC group and FSL [R(2) = 0.6; p = 0.1] for the PE1.5 and [R(2) = 0.6; p <; 0.01] for PE3 groups. The study demonstrates that the choice of the automated software for ICV estimation is dependent on the population under consideration and whether the software used is atlas-based or not.

Pathology and temporal onset of visual hallucinations, misperceptions and family misidentification distinguishes dementia with Lewy bodies from Alzheimer's disease.

OBJECTIVE: To determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer's disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features. METHODS: Consecutive cases of autopsy-confirmed LBD (n = 41), AD (n = 70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n = 14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed. RESULTS: The occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4-5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood dementia with Lewy bodies) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB. CONCLUSION: When visual hallucinations occur within the first 5 years of the dementia, a diagnosis of LBD was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.

Association of white matter hyperintensity measurements on brain MR imaging with cognitive status, medial temporal atrophy, and cardiovascular risk factors.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimer's Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.

Correction of coarctation of aorta in adult patients--impact of corrective procedure on long-term recoarctation and systolic hypertension.

BACKGROUND: Uncorrected coarctation of the aorta in adults predisposes to congestive failure, aortic rupture, stroke and endocarditis. Surgical correction of this condition is fraught with technical difficulties due to the complexity of the lesion, associated anomalies and extensive collaterals. The optimal surgical technique has not yet been well defined in adults. We describe our experience with adult coarctation and the long-term outcome with regard to recoarctation and systolic hypertension. MATERIALS AND METHODS: A consecutive series of 54 patients above the age of 12 years who underwent coarctation correction over a period of 8 years are included in this report. Eight patients underwent balloon angioplasty, one of whom also had stent placement. Forty-eight patients underwent surgical intervention. Twenty-seven patients underwent resection and anastomosis, 6 had patch angioplasty and 13 had a prosthetic graft repair. All patients were followed up at 3 months and then annually to look for recoarctation, regression of hypertension and aneurysm formation. RESULTS: There was no mortality in this series; major morbidities included reoperation for bleeding in 3 patients, pulmonary complications and paraplegia in 1 patient. Hypertension was well controlled in all patients at discharge. Follow-up is 100 % complete and mean follow-up was 4.6 years. There was one case of aortic dissection and one case of aneurysm formation in the balloon angioplasty group. There was a statistical trend towards increased rates of recoarctation in the balloon and resection and anastomosis groups. 32 % of patients were off antihypertensive medications at their last follow-up. CONCLUSIONS: Surgical correction of coarctation of aorta in adults can be achieved with an acceptable morbidity. A variety of options are available for the surgical management of coarctation of the aorta in adults. Prosthetic graft and patch repair are associated with good short and long-term results. Use of balloon angioplasty without stenting as the primary therapy requires further clarification. Hypertension is well controlled in most patients.

Atypical presentation of bilateral phrenic nerve palsy and its unusual recovery after coronary artery bypass grafting.

Bilateral phrenic nerve paralysis after coronary artery bypass surgery in a 47-year-old female patient is reported. This became evident on the 5th post-extubation day and mimicked acute coronary syndrome and led to difficulty in diagnosis. The patient required re-intubation and mechanical ventilation for only 6 days. The diagnosis of clinical and radiological abnormalities suggestive of bilateral phrenic nerve dysfunction was assisted by fluoroscopy, measurement of needle electromyography, and phrenic nerve motor conduction studies. The patient was followed up postoperatively for 14 weeks with complete regression of the neuropathy one month after surgery. An awareness of this complication should lead to improved care and successful postoperative management of patients.

Factors related to medication adherence in memory disorder clinic patients.

Medication adherence is a substantial problem in the elderly. It may be even more important among elderly persons with memory problems, since other factors that lead to non-adherence may be compounded with the memory problems themselves. The objective was to determine whether a model that integrates research on medication adherence from several research domains is useful in understanding adherence in elderly patients. The methodology involved a cross-sectional observational study using a convenience sample of 63 patients drawn from a university-affiliated outpatient memory disorders clinic. The primary measure of medication adherence was caregivers' reports of patients' medication adherence. Patients and their caregivers were asked questions assessing their beliefs about the seriousness of each condition for which a medication was prescribed and the likely outcome of that condition without treatment. Additional data collected included presence of side effects, total number of medications taken, and patients' mood and cognitive status. Multilevel path analysis confirmed several model-based predictions. Caregivers' reports of adherence were predicted by estimates of disease outcome, the presence of side effects, and patients' relying on themselves to remember to take medications. Results partially confirm the integrative model in understanding medication adherence in these patients. Patients' beliefs about the likely effect of medication treatment for their condition and the presence of side effects influence reported medication adherence. Results thus suggest that efforts to educate patients about the likely response of their medical condition to treatment and to assess and deal with medication side effects might improve patient adherence.

Family history of dementia is a risk factor for Lewy body disease.

Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

Mild cognitive impairment: directions for future research.

Mild cognitive impairment (MCI), an intermediate state between normal aging and dementia, is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Studies conducted on MCI have introduced new concepts regarding the possible distinctions between normal and pathologic aging of the brain. Neuroimaging and genetic testing have aided in the identification of individuals at increased risk for dementia. The measurement of change in cognitive and functional status in MCI remains challenging, because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. The authors provide an overview of the many methods that have been used to study MCI and directions that may help achieve greater uniformity in methodology. Considerable heterogeneity exists in research methodology used to study the epidemiology, thresholds for cognitive and functional impairment, rate of progression, risk factors, and defining subtypes of MCI. This article emphasizes the need for uniformity in the use of 1) appropriate and sensitive neuropsychological and functional measures to diagnose MCI, 2) reliable methods to determine progression or improvement of cognitive impairment, and 3) instruments in epidemiologic studies to establish population estimates for diverse ethnic and cultural groups. Greater consensus is needed to standardize definitions and research methodology for MCI, so as to make future studies more comparable and more useful for designing effective treatment strategies.

Confirmation of association between D10S583 and Alzheimer's disease in a case--control sample.

Several independent studies have reported that loci on chromosome 10 are associated/linked with Alzheimer's disease (AD), including a family-based study demonstrating an association between the marker D10S583 and AD. We have examined the D10S583 polymorphic marker and apolipoprotein E (APOE) gene in a case-control study. We observed the expected association of the APOE allele varepsilon4 with AD, and an inverse association between the D10S583 allele 209 and AD. These data support the original findings that suggest the presence of a candidate gene for AD in this region of chromosome 10. The nearby insulin degrading enzyme gene has been previously proposed as a candidate gene; however, a number of other putative candidate genes are also located in this region. The ongoing investigation of the genetic source of association and linkage in this region is clearly warranted.

Mutations in the open reading frame of the beta-site APP cleaving enzyme (BACE) locus are not a common cause of Alzheimer's disease.

Amyloid beta-peptide (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). The gene encoding the beta-site APP cleaving enzyme (BACE), one of two enzymes that sequentially cleave the beta-amyloid precursor protein to generate Abeta, has recently been cloned. We tested the hypothesis that BACE might be genetically associated with AD by linkage analysis (56 pedigrees), by direct nucleotide sequencing of the entire open reading frame (20 subjects with familial AD, and 10 subjects with sporadic AD) and by allelic association analysis (155 AD cases and 173 non-demented controls). Our results revealed no evidence for either genetic linkage or allelic association between BACE and AD, and no coding sequence mutations were detected in the open reading frame of the BACE gene. These data suggest that while BACE protein plays an important role in the pathogenesis of AD, and may be a robust therapeutic target, it is unlikely to be a major AD susceptibility locus.

Factor structure of the Cornell Scale for Depression in Dementia for Anglo and Hispanic patients with dementia.

The authors assessed the equivalence of the factor structure of the Cornell Scale for Depression in Dementia (CSDD) in samples of Anglo and Hispanic patients with Alzheimer's disease (AD). Comparing the factor structure of the CSDD in these groups helps establish its validity and aids in its clinical interpretation with Hispanic patients. CSDD ratings were first subjected to preliminary exploratory factor analyses; then the factor structure of the CSDD across groups of English- and Spanish-speaking patients was tested using structural equation modeling. Analyses showed overall similarity in the CSDD factor structure for the two groups but also revealed differences in factor content for several items. The authors discuss the relevance of these differences for those using the CSDD with Hispanic AD patients.

The Behavior Problems Checklist-Spanish: a preliminary study of a new scale for the assessment of depressive symptoms and disruptive behaviors in Hispanic patients with dementia.

Few instruments are available with which to measure behavioral and psychological signs and symptoms in Hispanic patients with dementia. Therefore, the aim of the current study was to develop and evaluate a 17-item scale adapted from the Revised Memory and Behavior Problems Checklist. This measure, the Behavior Problems Checklist-Spanish (BPC-S), assesses caregiver-reported symptoms of depression and disruption in patients with dementia. The sample for this study comprised 27 Spanish-speaking Hispanic patients and their family caregivers evaluated at a university-affiliated memory disorders center. All patients met diagnostic criteria for possible or probable Alzheimer's disease as set forth by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association. Satisfactory convergent validity, discriminant validity, and internal consistency reliability were demonstrated for the Depression and Disruption subscales of the BPC-S. Both of these neuropsychiatric disturbances were related to heightened levels of caregiver burden. The results of this preliminary study suggest the BPC-S is a brief, psychometrically sound caregiver-report instrument to assess symptoms of mood disturbance and behavioral disruption in Hispanic patients with dementia. This instrument may have utility for both clinical and research purposes.

Association between Alzheimer's disease and a functional polymorphism in the Myeloperoxidase gene.

A polymorphism in the Myeloperoxidase gene (MPO) has previously been demonstrated to be associated with gender-specific risk in an Alzheimer's Disease (AD) autopsy sample. We have investigated this polymorphism in our own samples of 226 Caucasian cases and 166 controls and 59 Hispanic cases and 75 controls. In Caucasians we find a significant association between MPO genotype and AD (P = 0.03), although we do not observe any effects of gender or any interaction with the APOE gene. Specifically, the MPO GG genotype contributes a 1.57-fold increased risk for AD. In Hispanics there was no effect of MPO genotype, or of MPO genotype in interaction with age or gender, on diagnosis of AD.

Category fluency test: normative data for English- and Spanish-speaking elderly.

Category fluency tasks are an important component of neuropsychological assessment, especially when evaluating for dementia syndromes. The growth in the number of Spanish-speaking elderly in the United States has increased the need for appropriate neuropsychological measures and normative data for this population. This study provides norms for English and Spanish speakers, over the age of 50, on 3 frequently used measures of category fluency: animals, vegetables, and fruits. In addition, it examines the impact of age, education, gender, language, and depressed mood on total fluency scores and on scores on each of these fluency measures. A sample of 702 cognitively intact elderly, 424 English speakers, and 278 Spanish speakers, participated in the study. Normative data are provided stratified by language, age, education, and gender. Results evidence that regardless of the primary language of the examinee, age, education, and gender are the strongest predictors of total category fluency scores, with gender being the best predictor of performance after adjusting for age and education. English and Spanish speakers obtained similar scores on animal and fruit fluency, but English speakers generated more vegetable exemplars than Spanish speakers. Results also indicate that different fluency measures are affected by various factors to different degrees.

Clinical characteristics of community-dwelling black Alzheimer's disease patients.

There is a relative dearth of studies examining the cognitive and neuropsychiatric features of black Alzheimer's disease (AD) patients in the United States. Therefore, this cross-sectional investigation reported on the prevalence and clinical correlates of depression and psychosis in a community-dwelling black AD sample. The study participants comprised 55 English-speaking black patients evaluated consecutively at a university-affiliated memory disorders clinic. All patients were evaluated utilizing standardized procedures and diagnosed with possible or probable AD according to the criteria established by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association. The presence of neuropsychiatric symptoms, including major depression and psychosis (delusions or hallucinations) was established via a semistructured psychiatric interview with the patient and primary care giver. The level of global cognitive impairment was rated with the Mini-Mental State Examination. The results showed that major depression and psychosis were observed in 20% and 58% of the sample, respectively. Mood disturbance was linked with low education, whereas psychosis was associated with greater cognitive dysfunction. This study provides important insight into the clinical characteristics of community-dwelling black AD patients. It is clear that continued research in the area of ethnicity and dementia is warranted to better understand the clinical needs of blacks and other minority populations in the United States that are afflicted with AD.

A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease.

OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD.

The genetic association between Cathepsin D and Alzheimer's disease.

The aspartyl protease Cathepsin D has previously been suggested to play a role in the Alzheimer's disease (AD) process because of its ability to cleave the beta-amyloid precursor protein and the possibility that it may be one of the 'secretase' enzymes. A functional C-->T polymorphism in the Cathepsin D gene (CATD) has been reported to be associated with increased risk for AD in Caucasian case-control studies; specifically, the T-carrying genotypes confer increased risk. We have examined this association in our own Caucasian dataset of 210 AD cases and 120 controls, and in an additional Hispanic dataset comprising 79 AD cases and 112 controls. In Hispanics we find a modest interaction between CATD genotype and age of onset on risk for AD, such that the non-T-carrying genotype confers increased risk. In our Caucasian dataset we find no evidence for association between the CATD polymorphism and AD, although we do observe a small tendency towards an increase in the T-carrying genotypes in the case group, consistent with previous studies. We conducted an aggregate analysis of the published Caucasian datasets and found evidence that this CATD polymorphism (or another locus in linkage disequilibrium) does contribute significant, but small (<2%) risk for AD.