Http Dx Doi Org 10 2105 Ajph 2011 300196, Aug 18, 2011
Hookah use is gaining popularity nationwide. We determined the correlates and trends for hookah u... more Hookah use is gaining popularity nationwide. We determined the correlates and trends for hookah use from the California Tobacco Survey. Between 2005 and 2008 hookah use increased more than 40%, and in 2008, 24.5% of young men reported ever using a hookah. Hookah use was more common among the young (18-24 years), the educated, the non-Hispanic Whites, and the cigarette smokers. Hookah use is increasing in California, especially among young adults, and in 2008 reached the highest prevalence ever reported for both genders.
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzhe... more Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months...
mer's disease (AD). Methods: Patients in our practice who were treated with combination therapy w... more mer's disease (AD). Methods: Patients in our practice who were treated with combination therapy with rivastigmine and memantine were evaluated. Patients met the DSM-IV and NINCDS-ADRDA criteria for possible Alzheimer's disease. Patients included in the study were treated with rivastigmine 12 mg / day in two divided doses. Memantine was started at 5 mg /day with dinner for one month. Dose was increases monthly by 5 mg /day to a maximum of 20 mg at two divided doses with rivastigmine (same time). Family and caregivers were educated about the possible benefits, side effects of the medications and realistic expectations. At baseline and after 24 weeks of treatment, subjective cognitive improvement, MMSE, ADL, and IADL outcomes were assessed and recorded. Caregivers were asked regarding tolerability, adverse events and clinical impression. Results: A total of 536 patients were evaluated. Average period of time patients were treated with combination therapy was 6.4 months. Average MMSE score was 18.3 (range 9 -26). Average time of treatment before baseline with rivastigmine was 14.2 months. No caregiver / family member reported cognitive deterioration during the six months of follow up. Adverse event was reported in 72 pts (13.4%). Average MMSE declined by 0.2 points after 6 months follow up. Two hundred and fifteen caregivers (40.1%) claimed there was a noticeable cognitive improvement while on combination therapy. Better functional performance was also reported in one hundred and seven (19.9%) patients. Average ADL / IADL scores improvement was 1.2/ 2.4 points during the follow up period. None of patients stopped treatment during 6 months of treatment. Conclusions: Combination therapy with rivastigmine (12 mg / day) with memantine (20 mg / day) is well tolerated. No adverse event was reported. None of caregivers reported any deterioration during 6 months of treatment.
Predisposition to sporadic Alzheimer&... more Predisposition to sporadic Alzheimer's disease (SAD) involves interactions between a person's unique combination of genetic variants and the environment. The molecular effect of these variants may be subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual's risk of developing SAD.
Theoretically, proton ((1)H) MR spectroscopy at a higher field strength has the advantages of hig... more Theoretically, proton ((1)H) MR spectroscopy at a higher field strength has the advantages of higher signal-to-noise ratio and improved spectral resolution. We therefore compared the ability of single-voxel (1)H MR spectroscopy at 1.5 and 3 T to diagnostically discriminate among cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). At both 1.5 and 3 T, we studied 41 cognitively normal elderly subjects, 20 patients with MCI, and 20 patients with AD. In each subject, (1)H MR spectroscopy was performed at TEs of 30 and 135 ms and from voxels placed over the posterior cingulate gyri. Average line widths and interexamination variability of metabolite ratios were higher at 3 T than at 1.5 T. Consistent quantification of glutamine (Gln) + glutamate/creatine (Cr) and Gln/Cr peak ratios occurred at 3 T but not at 1.5 T. Choline (Cho)/Cr (at TE = 135 ms) and myo-inositol (MI)/Cr were higher and N-acetylaspartate (NAA)/Cr ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2014
Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer'... more Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic s...
The Werner syndrome (WS) is characterized by the premature onset and accelerated rate of developm... more The Werner syndrome (WS) is characterized by the premature onset and accelerated rate of development of major geriatric disorders, including atherosclerosis, diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms. Cultures of WS skin-fibroblastlike cells have been previously shown to undergo accelerated rates of decline of their replicative potentials and to exhibit variegated chromosomal translocations and deletions. Since the replicative decline
Longitudinal studies of cognitive function in Alzheimer's disease (AD) patients are power... more Longitudinal studies of cognitive function in Alzheimer's disease (AD) patients are powerful tools to better understand the biology and natural history of the disease, but the attributes of the studies that make them valuable also pose special challenges to analysts. A fundamental problem is the accurate measure of time at which cognitive decline begins. Investigators typically use the date of AD diagnosis or the date of enrollment in an AD study. If the rate of cognitive decline is non-linear, variables associated with the time of diagnosis or enrollment might artificially be associated with the rate of decline. Unlike the mixed effects models typically used to analyse cognitive decline, summary measure analyses do not directly compare the rate of decline with time since decline began, and, therefore, are less sensitive to biased measures of time of decline. We simulated trajectories of cognitive decline using the multivariate normal random effect model and tested the ability of the two analytic techniques to discriminate between true and spurious associations. Our analyses suggest summary measure models are less likely to detect spurious associations generated by biased measures of time at which decline begins, and more likely to detect true associations concealed by biased time measurement.
To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we comp... more To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we compared the plasma cortisol and adrenocorticotropin (ACTS) responses to hypertonic saline infusion between normal older and young human volunteers. We administered a 90 min hypertonic saline infusion (5% sodium chloride at 0.06 mlikglmin) and a 90 min placebo infusion (0.9% sodium chloride at 0.06 ml/kg/min) to normal young subjects (n=13, age=2922 years) and normal older subjects (n=8, age=63 + 3 years). Plasma cortisol, ACTH, osmolality and arginine vasopressin (AVP) were measured before and at 30 min intervals during the infusions. The rate of increase in plasma osmolality and AVP induced by hypertonic saline infusion was similar between groups. The plasma cortisol increase during hypertonic saline infusion was greater in normal older subjects than in young subjects @=.03), but a stimulatory effect of hypertonic saline infusion on plasma ACTH was not apparent in either older or young subjects. These results suggest increased sensitivity with human aging to stimulation of cortisol release by hypertonic saline infusion at the adrenocortical level of the HPA axis.
To assess whether smoking ban policies are associated with smoking reduction and quit attempts am... more To assess whether smoking ban policies are associated with smoking reduction and quit attempts among California smokers. Data were examined for 1718 current smokers from follow-up telephone interviews conducted in 2011 of persons previously identified as smokers in a representative sample of the adult population of California. Population weighted logistic regressions controlling for demographic and other variables were used to evaluate the association between smoking ban policies (home, work, and town) and changes in tobacco use (past year quit attempt or reduction in smoking rate). Living in a home with a total ban was significantly associated with smoking reduction (adjusted odds ratio, AOR: 2.4, 95% CI: 1.4-4.2) and making a quit attempt (AOR: 2.3, 95% CI: 1.3-3.9) compared to living in a home with no home ban. Self-reported perception of an outdoor ban in one's city/town was associated with smoking reduction (AOR: 1.7, 95% CI: 1.02-2.7) and making a quit attempt (AOR: 1.8, 95% CI: 1.05-2.9). These results indicate that smoking bans not only protect nonsmokers from the harms of secondhand smoke, but are also associated with smoking reduction and cessation.
Genetic linkage studies have provided evidence for a late-onset Alzheimer&amp... more Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.
There is inadequate information regarding the neuropsychiatric aspect of Mild Cognitive Impairmen... more There is inadequate information regarding the neuropsychiatric aspect of Mild Cognitive Impairment (MCI). To determine the neuropsychiatric profile of MCI, and compare this with normal controls and patients with mild Alzheimer's Disease (AD). Cross-sectional assessment of psychiatric symptoms in subjects that are enrolled in Mayo Clinic's longitudinal study of normal aging, MCI and dementia. The Neuropsychiatric Inventory (NPI) was administered to normal control subjects, MCI subjects and patients with early AD. Individual NPI domain scores and total NPI scores were compared among the three groups after controlling for age, educational status, Dementia Rating Scale (DRS) and Mini-Mental State Examination (MMSE) scores. Statistical analysis was performed by utilizing ANOVA, chi2 and Fisher's exact test. Data were analyzed on 514 normal controls, 54 MCI subjects, and 87 subjects with mild AD (CDR of 0.5 or 1); females consisted of 60.3%, 53.7% and 57.5%; and, the average ages (SD) were 77.8 (1.95), 79 (4.6), 80.5 (14.6) respectively. ANOVA pair-wise comparison revealed that both MMSE and DRS differences among the three groups were significantly different at (p = 0.05). The total NPI scores were significantly different (p =0.0001, F = 107.93) among the three groups using ANOVA. Pair-wise comparison of individual behavioral domain of NPI showed statistically significant differences between MCI and normals; and MCI and AD (p = 0.001). Group differences on NPI remained after controlling for age and education at p = 0.0375 and p = 0.0050 respectively. The neuropsychiatric pattern is reminiscent of the clinical, neuroimaging and neuropsychological profile of MCI. It gives further credence to the view that MCI is indeed the gray zone, with overlap on both ends of the pole.
The Werner syndrome (WS) is characterized by the premature onset and accelerated rates of develop... more The Werner syndrome (WS) is characterized by the premature onset and accelerated rates of development of major geriatric disorders, including atherosclerosis, diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms. Cultures of WS skin-fibroblastlike cells have been previously shown to undergo accelerated rates of decline of their replicative potentials and to exhibit variegated chromosomal translocations and deletions. Since the replicative decline of normal somatic cells is associated with a loss of telomeric repeats, we investigated the kinetics of telomeric repeat loss in WS cells. The mean length of telomere restriction fragments (TRF) from the earliest passages of WS cells studied was not shorter than those of controls, possibly reflecting selective pressure for subsets of cells with relatively high residual replicative capacity. Statistical evidence indicated an accelerated shortening of TRF length in serially passaged WS cultures, but the mean TRF lengths of WS cultures that had ceased replicating were significantly longer than those of senescent controls. Thus, while accelerated loss of telomeric repeats could potentially explain the rapid decline in proliferation of WS cells, it is possible that WS cells exit the cell cycle via mechanisms that differ from those of replicatively senescent cells from control subjects.
This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, s... more This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel (SV) 1 H MR Spectroscopy (MRS) and MR diffusion weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI, and 22 AD patients underwent MR-based hippocampal volumetry, 1 H MRS, and DWI. 1 H MRS voxels were placed over both of the posterior cingulate gyri and N-acetyl aspartate (NAA) / creatine (Cr), myoinositol (MI) /Cr and NAA /MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79 %) and AD (86 %) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA /Cr (67 %). At high specificity (>85 -90%) combinations of MR measures had superior diagnostic sensitivity compared to any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.
The Mini-Mental State Examination (MMSE) is the most widely used brief screening measure of cogni... more The Mini-Mental State Examination (MMSE) is the most widely used brief screening measure of cognition, but it is not sensitive in detecting mild memory or other cognitive impairments. The Short Test of Mental Status (STMS) was specifically developed for use in dementia assessment and was intended to be more sensitive to problems of learning and mental agility that may be seen in mild cognitive impairment (MCI). To compare the STMS and MMSE for detecting or predicting MCI. Comparison of STMS and MMSE scores at baseline among 4 groups of patients: 788 patients with stable normal cognition, 75 patients with normal cognition at baseline but who developed incident MCI or Alzheimer disease during follow-up, 129 patients with prevalent MCI at baseline, and 235 patients with prevalent mild Alzheimer disease. All patients and control subjects for this study were evaluated through the Mayo Alzheimer's Disease Patient Registry or the Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minn, using a standardized diagnostic approach. The STMS was slightly more sensitive than the MMSE in discriminating between patients with stable normal cognition and patients with prevalent MCI. The STMS was superior to the MMSE in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease. Compared with the MMSE, the STMS was better able to document MCI and was more sensitive in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease.
The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutation... more The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutations, all of which result in the truncation of the protein, lead to Werner syndrome. However, little is known about the role of WRN in "normal" aging. We have identified four missense polymorphisms and four conservative polymorphsims in WRN gene. A single study showed that a polymorphism at amino acid 1367 Cys(TTG)/ Arg(CTG) is associated with a variation in risk of myocardial infarction among a Japanese population. The 1367 Cys/Arg polymorphism was examined during aging in three different populations: Finnish, Mexican, and North American. The frequencies of 1367 Cys were higher than those of 1367 Arg in all the populations examined, though the frequencies varied among populations. The frequency of the 1367 Arg allele, thought to be protective against myocardial infarction in a Japanese population, was approximately three times higher in the North American and Finnish adult populations. When newborns and centenarians were compared within the Finnish population, no differences were observed in the proportions of 1367 Cys/Arg across age groups. Within the Finnish population, we confirmed a significant decrease of the APOE epsilon2 allele and an increase in the epsilon4 allele in newborn infants compared with centenarians. Thus, unlike the APOE polymorphism, there is no evidence of an association of this WRN polymorphism with longevity.
The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the pr... more The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.
Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the ... more Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/ Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process.
Background: Knowledge of which factors influence retention rates in clinical trials may inform re... more Background: Knowledge of which factors influence retention rates in clinical trials may inform recruitment and retention strategies of future clinical trials. Studies with a low dropout rate have increased statistical power. A low dropout rate also reduces the chance of informative censoring. Hence, focused retention efforts may improve a trial's power and validity. Objective: To better understand the influence of baseline characteristics on dropout rates in secondary prevention trials testing treatments to delay conversion from mild cognitive impairment (MCI) to Alzheimer's disease. Methods: Subjects are 769 participants from 69 sites enrolled in a three year secondary prevention trial conducted by the Alzheimer's Disease Cooperative Study (supported by a grant from the National Institute on Aging (UO1-AG104083), the Institute for the Study of Aging, Pfizer Inc, and Easai Inc). Analysis was by Cox proportional hazards regression. Baseline characteristics significant at the 0.10 level in univariate analyses were considered for inclusion in a final multivariate model. Results: A total of 230 subjects (29%) discontinued for reasons other than death or conversion to dementia. Age, marital status, informant relationship, gender, education, and race were significant predictors of dropout in univariate analyses. In multivariate analysis, risk of dropout remained significantly higher (pϽ0.05) among non-white subjects and among subjects with less than college education. Conclusions: Dropout rates were higher among minorities and those with less education. Retention efforts focused on these areas may improve the statistical power and validity of secondary prevention trials.
Http Dx Doi Org 10 2105 Ajph 2011 300196, Aug 18, 2011
Hookah use is gaining popularity nationwide. We determined the correlates and trends for hookah u... more Hookah use is gaining popularity nationwide. We determined the correlates and trends for hookah use from the California Tobacco Survey. Between 2005 and 2008 hookah use increased more than 40%, and in 2008, 24.5% of young men reported ever using a hookah. Hookah use was more common among the young (18-24 years), the educated, the non-Hispanic Whites, and the cigarette smokers. Hookah use is increasing in California, especially among young adults, and in 2008 reached the highest prevalence ever reported for both genders.
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzhe... more Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months...
mer's disease (AD). Methods: Patients in our practice who were treated with combination therapy w... more mer's disease (AD). Methods: Patients in our practice who were treated with combination therapy with rivastigmine and memantine were evaluated. Patients met the DSM-IV and NINCDS-ADRDA criteria for possible Alzheimer's disease. Patients included in the study were treated with rivastigmine 12 mg / day in two divided doses. Memantine was started at 5 mg /day with dinner for one month. Dose was increases monthly by 5 mg /day to a maximum of 20 mg at two divided doses with rivastigmine (same time). Family and caregivers were educated about the possible benefits, side effects of the medications and realistic expectations. At baseline and after 24 weeks of treatment, subjective cognitive improvement, MMSE, ADL, and IADL outcomes were assessed and recorded. Caregivers were asked regarding tolerability, adverse events and clinical impression. Results: A total of 536 patients were evaluated. Average period of time patients were treated with combination therapy was 6.4 months. Average MMSE score was 18.3 (range 9 -26). Average time of treatment before baseline with rivastigmine was 14.2 months. No caregiver / family member reported cognitive deterioration during the six months of follow up. Adverse event was reported in 72 pts (13.4%). Average MMSE declined by 0.2 points after 6 months follow up. Two hundred and fifteen caregivers (40.1%) claimed there was a noticeable cognitive improvement while on combination therapy. Better functional performance was also reported in one hundred and seven (19.9%) patients. Average ADL / IADL scores improvement was 1.2/ 2.4 points during the follow up period. None of patients stopped treatment during 6 months of treatment. Conclusions: Combination therapy with rivastigmine (12 mg / day) with memantine (20 mg / day) is well tolerated. No adverse event was reported. None of caregivers reported any deterioration during 6 months of treatment.
Predisposition to sporadic Alzheimer&... more Predisposition to sporadic Alzheimer's disease (SAD) involves interactions between a person's unique combination of genetic variants and the environment. The molecular effect of these variants may be subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual's risk of developing SAD.
Theoretically, proton ((1)H) MR spectroscopy at a higher field strength has the advantages of hig... more Theoretically, proton ((1)H) MR spectroscopy at a higher field strength has the advantages of higher signal-to-noise ratio and improved spectral resolution. We therefore compared the ability of single-voxel (1)H MR spectroscopy at 1.5 and 3 T to diagnostically discriminate among cognitively normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with Alzheimer disease (AD). At both 1.5 and 3 T, we studied 41 cognitively normal elderly subjects, 20 patients with MCI, and 20 patients with AD. In each subject, (1)H MR spectroscopy was performed at TEs of 30 and 135 ms and from voxels placed over the posterior cingulate gyri. Average line widths and interexamination variability of metabolite ratios were higher at 3 T than at 1.5 T. Consistent quantification of glutamine (Gln) + glutamate/creatine (Cr) and Gln/Cr peak ratios occurred at 3 T but not at 1.5 T. Choline (Cho)/Cr (at TE = 135 ms) and myo-inositol (MI)/Cr were higher and N-acetylaspartate (NAA)/Cr ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2014
Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer'... more Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic s...
The Werner syndrome (WS) is characterized by the premature onset and accelerated rate of developm... more The Werner syndrome (WS) is characterized by the premature onset and accelerated rate of development of major geriatric disorders, including atherosclerosis, diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms. Cultures of WS skin-fibroblastlike cells have been previously shown to undergo accelerated rates of decline of their replicative potentials and to exhibit variegated chromosomal translocations and deletions. Since the replicative decline
Longitudinal studies of cognitive function in Alzheimer's disease (AD) patients are power... more Longitudinal studies of cognitive function in Alzheimer's disease (AD) patients are powerful tools to better understand the biology and natural history of the disease, but the attributes of the studies that make them valuable also pose special challenges to analysts. A fundamental problem is the accurate measure of time at which cognitive decline begins. Investigators typically use the date of AD diagnosis or the date of enrollment in an AD study. If the rate of cognitive decline is non-linear, variables associated with the time of diagnosis or enrollment might artificially be associated with the rate of decline. Unlike the mixed effects models typically used to analyse cognitive decline, summary measure analyses do not directly compare the rate of decline with time since decline began, and, therefore, are less sensitive to biased measures of time of decline. We simulated trajectories of cognitive decline using the multivariate normal random effect model and tested the ability of the two analytic techniques to discriminate between true and spurious associations. Our analyses suggest summary measure models are less likely to detect spurious associations generated by biased measures of time at which decline begins, and more likely to detect true associations concealed by biased time measurement.
To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we comp... more To assess the effects of aging on hypothalamic-pituitary-adrenal (HPA) axis responsivity, we compared the plasma cortisol and adrenocorticotropin (ACTS) responses to hypertonic saline infusion between normal older and young human volunteers. We administered a 90 min hypertonic saline infusion (5% sodium chloride at 0.06 mlikglmin) and a 90 min placebo infusion (0.9% sodium chloride at 0.06 ml/kg/min) to normal young subjects (n=13, age=2922 years) and normal older subjects (n=8, age=63 + 3 years). Plasma cortisol, ACTH, osmolality and arginine vasopressin (AVP) were measured before and at 30 min intervals during the infusions. The rate of increase in plasma osmolality and AVP induced by hypertonic saline infusion was similar between groups. The plasma cortisol increase during hypertonic saline infusion was greater in normal older subjects than in young subjects @=.03), but a stimulatory effect of hypertonic saline infusion on plasma ACTH was not apparent in either older or young subjects. These results suggest increased sensitivity with human aging to stimulation of cortisol release by hypertonic saline infusion at the adrenocortical level of the HPA axis.
To assess whether smoking ban policies are associated with smoking reduction and quit attempts am... more To assess whether smoking ban policies are associated with smoking reduction and quit attempts among California smokers. Data were examined for 1718 current smokers from follow-up telephone interviews conducted in 2011 of persons previously identified as smokers in a representative sample of the adult population of California. Population weighted logistic regressions controlling for demographic and other variables were used to evaluate the association between smoking ban policies (home, work, and town) and changes in tobacco use (past year quit attempt or reduction in smoking rate). Living in a home with a total ban was significantly associated with smoking reduction (adjusted odds ratio, AOR: 2.4, 95% CI: 1.4-4.2) and making a quit attempt (AOR: 2.3, 95% CI: 1.3-3.9) compared to living in a home with no home ban. Self-reported perception of an outdoor ban in one's city/town was associated with smoking reduction (AOR: 1.7, 95% CI: 1.02-2.7) and making a quit attempt (AOR: 1.8, 95% CI: 1.05-2.9). These results indicate that smoking bans not only protect nonsmokers from the harms of secondhand smoke, but are also associated with smoking reduction and cessation.
Genetic linkage studies have provided evidence for a late-onset Alzheimer&amp... more Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.
There is inadequate information regarding the neuropsychiatric aspect of Mild Cognitive Impairmen... more There is inadequate information regarding the neuropsychiatric aspect of Mild Cognitive Impairment (MCI). To determine the neuropsychiatric profile of MCI, and compare this with normal controls and patients with mild Alzheimer's Disease (AD). Cross-sectional assessment of psychiatric symptoms in subjects that are enrolled in Mayo Clinic's longitudinal study of normal aging, MCI and dementia. The Neuropsychiatric Inventory (NPI) was administered to normal control subjects, MCI subjects and patients with early AD. Individual NPI domain scores and total NPI scores were compared among the three groups after controlling for age, educational status, Dementia Rating Scale (DRS) and Mini-Mental State Examination (MMSE) scores. Statistical analysis was performed by utilizing ANOVA, chi2 and Fisher's exact test. Data were analyzed on 514 normal controls, 54 MCI subjects, and 87 subjects with mild AD (CDR of 0.5 or 1); females consisted of 60.3%, 53.7% and 57.5%; and, the average ages (SD) were 77.8 (1.95), 79 (4.6), 80.5 (14.6) respectively. ANOVA pair-wise comparison revealed that both MMSE and DRS differences among the three groups were significantly different at (p = 0.05). The total NPI scores were significantly different (p =0.0001, F = 107.93) among the three groups using ANOVA. Pair-wise comparison of individual behavioral domain of NPI showed statistically significant differences between MCI and normals; and MCI and AD (p = 0.001). Group differences on NPI remained after controlling for age and education at p = 0.0375 and p = 0.0050 respectively. The neuropsychiatric pattern is reminiscent of the clinical, neuroimaging and neuropsychological profile of MCI. It gives further credence to the view that MCI is indeed the gray zone, with overlap on both ends of the pole.
The Werner syndrome (WS) is characterized by the premature onset and accelerated rates of develop... more The Werner syndrome (WS) is characterized by the premature onset and accelerated rates of development of major geriatric disorders, including atherosclerosis, diabetes mellitus, osteoporosis, ocular cataracts, and various neoplasms. Cultures of WS skin-fibroblastlike cells have been previously shown to undergo accelerated rates of decline of their replicative potentials and to exhibit variegated chromosomal translocations and deletions. Since the replicative decline of normal somatic cells is associated with a loss of telomeric repeats, we investigated the kinetics of telomeric repeat loss in WS cells. The mean length of telomere restriction fragments (TRF) from the earliest passages of WS cells studied was not shorter than those of controls, possibly reflecting selective pressure for subsets of cells with relatively high residual replicative capacity. Statistical evidence indicated an accelerated shortening of TRF length in serially passaged WS cultures, but the mean TRF lengths of WS cultures that had ceased replicating were significantly longer than those of senescent controls. Thus, while accelerated loss of telomeric repeats could potentially explain the rapid decline in proliferation of WS cells, it is possible that WS cells exit the cell cycle via mechanisms that differ from those of replicatively senescent cells from control subjects.
This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, s... more This study compares diagnostic accuracy of magnetic resonance (MR)-based hippocampal volumetry, single voxel (SV) 1 H MR Spectroscopy (MRS) and MR diffusion weighted imaging (DWI) measurements in discriminating patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease (AD) and normally aging elderly. Sixty-one normally aging elderly, 24 MCI, and 22 AD patients underwent MR-based hippocampal volumetry, 1 H MRS, and DWI. 1 H MRS voxels were placed over both of the posterior cingulate gyri and N-acetyl aspartate (NAA) / creatine (Cr), myoinositol (MI) /Cr and NAA /MI ratios were obtained. Apparent diffusion coefficient (ADC) maps were derived from DWI and hippocampal borders were traced to measure hippocampal ADC. At 80% specificity, the most sensitive single measurement to discriminate MCI (79 %) and AD (86 %) from controls was hippocampal volumes. The most sensitive single measurement to discriminate AD from MCI was posterior cingulate gyrus NAA /Cr (67 %). At high specificity (>85 -90%) combinations of MR measures had superior diagnostic sensitivity compared to any single MR measurement for the AD vs. control and control vs. MCI comparisons. The MR measures that best discriminate more from less affected individuals along the cognitive continuum from normal to AD vary with disease severity. Selection of imaging measures used for clinical assessment or monitoring efficiency of therapeutic intervention should be tailored to the clinical stage of the disease.
The Mini-Mental State Examination (MMSE) is the most widely used brief screening measure of cogni... more The Mini-Mental State Examination (MMSE) is the most widely used brief screening measure of cognition, but it is not sensitive in detecting mild memory or other cognitive impairments. The Short Test of Mental Status (STMS) was specifically developed for use in dementia assessment and was intended to be more sensitive to problems of learning and mental agility that may be seen in mild cognitive impairment (MCI). To compare the STMS and MMSE for detecting or predicting MCI. Comparison of STMS and MMSE scores at baseline among 4 groups of patients: 788 patients with stable normal cognition, 75 patients with normal cognition at baseline but who developed incident MCI or Alzheimer disease during follow-up, 129 patients with prevalent MCI at baseline, and 235 patients with prevalent mild Alzheimer disease. All patients and control subjects for this study were evaluated through the Mayo Alzheimer's Disease Patient Registry or the Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minn, using a standardized diagnostic approach. The STMS was slightly more sensitive than the MMSE in discriminating between patients with stable normal cognition and patients with prevalent MCI. The STMS was superior to the MMSE in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease. Compared with the MMSE, the STMS was better able to document MCI and was more sensitive in detecting deficits in cognition in individuals who had normal cognition at baseline but later developed incident MCI or Alzheimer disease.
The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutation... more The Werner syndrome gene (WRN) encodes a novel helicase of 1,432 amino acids. Homozygous mutations, all of which result in the truncation of the protein, lead to Werner syndrome. However, little is known about the role of WRN in "normal" aging. We have identified four missense polymorphisms and four conservative polymorphsims in WRN gene. A single study showed that a polymorphism at amino acid 1367 Cys(TTG)/ Arg(CTG) is associated with a variation in risk of myocardial infarction among a Japanese population. The 1367 Cys/Arg polymorphism was examined during aging in three different populations: Finnish, Mexican, and North American. The frequencies of 1367 Cys were higher than those of 1367 Arg in all the populations examined, though the frequencies varied among populations. The frequency of the 1367 Arg allele, thought to be protective against myocardial infarction in a Japanese population, was approximately three times higher in the North American and Finnish adult populations. When newborns and centenarians were compared within the Finnish population, no differences were observed in the proportions of 1367 Cys/Arg across age groups. Within the Finnish population, we confirmed a significant decrease of the APOE epsilon2 allele and an increase in the epsilon4 allele in newborn infants compared with centenarians. Thus, unlike the APOE polymorphism, there is no evidence of an association of this WRN polymorphism with longevity.
The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the pr... more The Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus (NIDDM), ocular cataracts and osteoporosis [Epstein et al., 1966]. The major cause of death (at a median age of 47) is myocardial infarction (MI) [Epstein et al., 1966]. The WS mutation involves a member (WRN) of the RecQ family of helicases and may perturb DNA replication, repair, recombination, transcription, or chromosomal segregation [Yu et al., 1996]. We now report data on 149 MI cases and age-matched controls suggesting that a polymorphic WRN variant is associated with increased risk for MI. Based on our data, homozygosity for a cysteine at amino acid 1367 (the most prevalent genotype) predicts a 2.78 times greater risk of MI (95% confidence intervals: 1.23 to 6.86). The variant was not significantly associated with NIDDM. The two alleles (cysteine vs. arginine) could influence helicase activity, turnover, macromolecular interactions or, alternatively, could be markers for haplotypes influencing WRN regulation or reflecting gene action at linked loci. However, given the caveats implicit in genetic association studies, it is imperative that the present results be replicated in independent populations.
Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the ... more Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/ Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process.
Background: Knowledge of which factors influence retention rates in clinical trials may inform re... more Background: Knowledge of which factors influence retention rates in clinical trials may inform recruitment and retention strategies of future clinical trials. Studies with a low dropout rate have increased statistical power. A low dropout rate also reduces the chance of informative censoring. Hence, focused retention efforts may improve a trial's power and validity. Objective: To better understand the influence of baseline characteristics on dropout rates in secondary prevention trials testing treatments to delay conversion from mild cognitive impairment (MCI) to Alzheimer's disease. Methods: Subjects are 769 participants from 69 sites enrolled in a three year secondary prevention trial conducted by the Alzheimer's Disease Cooperative Study (supported by a grant from the National Institute on Aging (UO1-AG104083), the Institute for the Study of Aging, Pfizer Inc, and Easai Inc). Analysis was by Cox proportional hazards regression. Baseline characteristics significant at the 0.10 level in univariate analyses were considered for inclusion in a final multivariate model. Results: A total of 230 subjects (29%) discontinued for reasons other than death or conversion to dementia. Age, marital status, informant relationship, gender, education, and race were significant predictors of dropout in univariate analyses. In multivariate analysis, risk of dropout remained significantly higher (pϽ0.05) among non-white subjects and among subjects with less than college education. Conclusions: Dropout rates were higher among minorities and those with less education. Retention efforts focused on these areas may improve the statistical power and validity of secondary prevention trials.
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Papers by Steven Edland