SYNOPSISEndothelins are a recently discovered group of potent vasoconstrictor peptides synthesized by endothelial cells and other tissues in various species, which seem to participate in the regulation of vascular tonus. Abnormalities in... more
SYNOPSISEndothelins are a recently discovered group of potent vasoconstrictor peptides synthesized by endothelial cells and other tissues in various species, which seem to participate in the regulation of vascular tonus. Abnormalities in vasoactivity in the head may be an important event in headache pathophysiology, although the mechanisms responsible for such constrictions and/or dilations are not known. The endothelium and its constrictor peptide, endothelin, may play a key role in such mechanisms. Of the various drugs used in the treatment of headache, lithium is an accepted treatment for cluster headache, and indomethacin is the drug of choice for the associated condition chronic paroxysmal hemicrania. The mechanism of action of these drugs in these headaches is not known. Due to the possible involvement of endothelin in headache disorders, the objective of this study was to verify the effects of lithium and cyclooxygenase inhibitors (indomethacin, acetylsalicylic acid and naproxen) on endothelin‐1 (ET‐1)‐induced contractions in isolated human temporal arteries and porcine ophthalmic arteries. It was found that all drugs increased the (ET‐1)‐induced contractions in human temporal arteries. Conversely, there were no significant changes induced by the drugs in porcine ophthalmic arteries. These results are consistent with the variation of activity often seen in different vascular beds and between species. The potential importance of such reactions for the understanding of vascular changes putatively involved in headache development and treatment is discussed.
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Research Interests: Dementia, Magnetic Resonance Imaging, Medicine, Comorbidity, Humans, and 15 moreCaudate Nucleus, Male, Hawaii, Cognitive Performance, Clinical Sciences, Brain atrophy, Cognitive impairment, Asian Americans, Cognitive Ability, Degeneration, Cognitive Function, Cognitive Decline, Cognition disorders, Magnetic resonance image, and Corpus striatum
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Objective: To investigate the relationship of amyloid neuropathology to postmortem CSF Aβ 42 levels in an autopsy sample of Japanese American men from the population-based Honolulu–Asia Aging Study.Methods: In 1991, participants were... more
Objective: To investigate the relationship of amyloid neuropathology to postmortem CSF Aβ 42 levels in an autopsy sample of Japanese American men from the population-based Honolulu–Asia Aging Study.Methods: In 1991, participants were assessed and diagnosed with dementia (including subtype) based on published criteria. At death CSF was obtained from the ventricles. Neuritic plaques (NP) and diffuse plaques in areas of the neocortex and hippocampus were examined using Bielschowsky silver stains. Cerebral amyloid angiopathy (CAA) was measured by immunostaining for β4 amyloid in cerebral vessels in the neocortex. Neuropathologically confirmed AD was diagnosed using Consortium to Establish a Registry for Alzheimer’s Disease criteria. In 155 autopsy samples, log transformed linear regression models were used to examine the association of NP and CAA to Aβ 42 levels, controlling for clinical dementia severity, time between diagnosis and death, age at death, brain weight, hours between death and collection of CSF, education, and APOE genotype.Results: Higher numbers of NP in the neocortex (p trend = 0.001) and in the hippocampus (p trend = 0.03) were strongly associated with lower levels of Aβ 42. Individuals with CAA had lower Aβ 42 levels (β coefficient = −0.48; 95% CI −0.9, −0.1). Compared to participants with a diagnosis of clinical dementia, those with pathologically confirmed AD had lower Aβ 42 levels (β coefficient = −0.74; 95% CI −1.4, −0.1).Conclusion: The current study suggests that lower Aβ 42 levels reflect neuropathologic processes implicated in amyloid-related pathologies, such as NP and CAA.
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While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer’s Disease and Related... more
While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer’s Disease and Related Dementias (ADRD). Published analytic conclusions have been mixed. Two reports in the Journal of Alzheimer’s Disease reach the same answer: a history of brain injury appears to be a risk factor for generalized brain atrophy, which would likely increase vulnerability to the subsequent development of any variety of ADRD, or to dementia directly attributable to reduced brain mass.
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>90 years) and performed cox regression analyses. Results:Mean age at inclusion was 72.4 years (SD 7.5, range 65-115 years), 45.7% were male, and median follow-up was 3.7 years (IQR 1.95.7). The follow-up was similar between... more
>90 years) and performed cox regression analyses. Results:Mean age at inclusion was 72.4 years (SD 7.5, range 65-115 years), 45.7% were male, and median follow-up was 3.7 years (IQR 1.95.7). The follow-up was similar between individuals with and without vascular disorders. During 1.5 million person years of follow-up, 12,362 individuals developed dementia and 41,586 died. Hypertension was associated with lower dementia risk at all ages (Fig 1.). For all other disorders, the risk for dementia was higher at young age than at high age. Hypertension was associated with decreased mortality while all other vascular disorders had an increased risk for death, regardless of age (Fig. 2). Cox regression analyses after correction for age and gender yielded similar results. Conclusions:The risk of vascular disorders for dementia decreases with higher age, in line with population-based studies. Competing risk of mortality may not be an explanation as mortality was decreased in hypertensive individuals and increased in individuals with other vascular pathology regardless of age. Moreover, followup time was similar in individuals with and without vascular disorders. Alternatively, general practitioners may under-diagnose dementia in individuals with vascular diseases or treatment of a clinical diagnosis of vascular disorders may reduce dementia risk. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking EMIF grant agreement no. 115372.
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An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to... more
An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to integrate information about molecular biology, neuropathology, behavioral aspects of cognitive decline, and cognitive resilience will be of particular importance. Additionally, more work is needed to improve our understanding of the effect of systemic factors on brain health and function. It seems likely that, even in later life, the brain’s plasticity may allow for a positive response to stimulation. The ultimate goal of this research is to create a validated set of variables and interventions—and to understand the biology underlying them—that are useful not only in describing an individual’s cognitive state but also in identifying promising paths for treatment and prevention of cognitive decline.
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Mortality and hospitalization rates for pneumonia have increased among older Americans during recent years (1979-86), despite a national commitment to the reduction of premature deaths from pneumonia. A prospective study of deaths and... more
Mortality and hospitalization rates for pneumonia have increased among older Americans during recent years (1979-86), despite a national commitment to the reduction of premature deaths from pneumonia. A prospective study of deaths and hospitalizations attributable to pneumonia was conducted among 5,474 subjects ages 55 and older who participated in the NHANES I Epidemiologic Followup Study. Prevalent chronic conditions, health behaviors, and nutritional status indicators, measured at baseline, were examined in relation to pneumonia hospitalization and death during 12 years of followup. Mortality and hospitalization rates for pneumonia were higher among men than women, and higher among those ages 65 and older than among those 55-64 of both sexes. Risk of pneumonia death was higher among subjects with a history of congestive heart failure, stroke, cancer, or diabetes. Risk of pneumonia hospitalization was higher among subjects with a history of chronic obstructive pulmonary disease and among men who were current smokers. Daily alcohol consumption did not increase risk of pneumonia in this study population. Four measures of nutritional status were examined taking age, prevalent chronic conditions, and cigarette smoking into account: body mass index, arm muscle area, and serum albumin and hemoglobin levels. Risk of pneumonia death was 2.6 times higher in men in the lowest quartile, compared with men in the highest quartile, of body mass index. Similarly, the risk was 4.5 times higher among men in the lowest quartile of arm muscle area. Risk of death from pneumonia was 3.6 times higher among women in the lowest quartile of serum albumin levels compared with women in the highest quartile. Relative risks for these nutritional status indicators remained elevated after adjusting for age and the medical history risk factors. These risk factors should be taken into account when designing and evaluating pneumonia vaccination trials and community prevention programs.
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pathology; the other major pathological marker of Alzheimer’s Disease (AD). Our initial studies document that TLR9 signaling with the type B CpG ODN has a beneficial effect in 3xTg-AD mice with both plaque and tangle pathology without... more
pathology; the other major pathological marker of Alzheimer’s Disease (AD). Our initial studies document that TLR9 signaling with the type B CpG ODN has a beneficial effect in 3xTg-AD mice with both plaque and tangle pathology without toxicity, suggesting that stimulating the innate immunity has the possible advantage of concurrently addressing both AD pathologies. Given the importance of tau related pathology, we felt it was critical to more precisely determine the effect of our novel approach in rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concomitant Ab pathology. Methods: The rTg4510 mice were injected with either the TLR9 agonist class B CpG ODN or saline at monthly intervals (from 3 to 11 months of age). After the treatment the mice were subjected to behavioral testing. Histological analyses commenced upon completion of the behavioral protocol. Animals were continuously monitored for signs of toxicity.Results:Administration of CpGODNwas effective at improving spatial working memory evaluated using the closed field symmetrical maze in rTg4510 mice. No difference between groups was found in any of the locomotor parameters. Histological evaluation of CpG ODN effect on hippocampal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG ODN-treated animals. Although the effect on tau pathology was modest, our findings confirmed that this type of immunomodulation has beneficial effects on tau related pathology, in contrast to number of other prior innate immunity stimulation approaches. Biochemical assessments of tau levels are underway. No differences were noted in the extent of CD45 microgliosis and GFAP astrogliosis in CpG ODN-treated animals compared to controls, at the end of the treatment. In addition, we have preliminary data showing that acute injection of CpG ODN leads to an induction of favorable microglia/macrophage activation in rTg4510 mice. Further characterization of immune responses is ongoing. Conclusions:Overall, the present findings, together with our earlier research, represent essential preclinical evidence validating the feasibility of TLR9 ligand CpG ODN as a disease modifying drug for AD.
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Summary A semiquantitative assay for endogenous pyrogen in serum is described. The test depends on using at least 3-4 recipients at at least 4 ranges of dosage, and the use of the fever index rather than height of the fever curve. This... more
Summary A semiquantitative assay for endogenous pyrogen in serum is described. The test depends on using at least 3-4 recipients at at least 4 ranges of dosage, and the use of the fever index rather than height of the fever curve. This permits construction of a dose response curve which delineates the sensitive range of pyrexia. The minimum pyrogenic dose can then be calculated and should serve as a useful standard for comparison of different pyrogenic substances.
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Research Interests: Psychology, Resilience, Dementia, Cognition, Adaptation, and 15 moreAging, Cognitive reserve, Medicine, Prevention, Neurodegenerative Diseases, Brain, Humans, Psychological, Resistance, Psychological Intervention, Reserve capacity, Behavioral and Social Science Research, Neurosciences, Brain Disorders, and Medical and Health Sciences
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To determine the prevalence and cessation of driving among older men with incident dementia in the Honolulu-Asia Aging Study. Retrospective cohort data from a community-based study of incident dementia. The Honolulu Heart Program and the... more
To determine the prevalence and cessation of driving among older men with incident dementia in the Honolulu-Asia Aging Study. Retrospective cohort data from a community-based study of incident dementia. The Honolulu Heart Program and the Honolulu-Asia Aging Study. A total of 643 men who were evaluated for the incidence of Alzheimer's disease or other dementia between the fourth and the fifth examination of the Honolulu Heart Program. Driving history, diagnosis of dementia, grip strength, walking speed, standing balance test, interviewer's rating of vision status, and the neurologist's notes on mentions of driving behavior from informal interviews with a caregiver or family informant. The prevalence of driving declined dramatically with level of cognitive functioning. Among 162 men evaluated and found to have normal cognitive functioning, 78% still drove, compared with 62% of 287 men with poor cognitive functioning but no clinical dementia, 46% of 96 men with a new diagnosis of very mild dementia (Clinical Dementia Rating = 0.5), and 22% of 98 men with a new diagnosis of mild dementia (CDR = 1). Only one of 23 men diagnosed with moderate or more severe staged incident dementia (CDR > 1) was driving. About 10% of the 59 demented persons still driving relied on co-pilots, and only one driver was reported as involved in a crash according to a review of the neurologists' notes. Incident dementia is a major cause of driving cessation. Based on these data, we estimate that approximately 4% of male drivers aged 75 years and older nationwide (about 175,000 men) have dementia. This number will increase with the projected growth of drivers aged 75 years and older.
Research Interests: Dementia, Cognition, Medicine, Activities of Daily Living, Humans, and 15 moreMale, Hawaii, Incidence, Aged, Prevalence, Questionnaires, Retrospective Studies, Geriatric Assessment, Logistic Models, The American, Automobile driving, mass Screening, Medical and Health Sciences, Hand strength, and Age distribution
Research Interests: Health Promotion, Dementia, Aging, Medicine, Humans, and 15 moreHypertension, Blood Pressure, Male, Confidence intervals, Hawaii, Cohort, Clinical Sciences, Middle Aged, Age Factors, Cognition disorders, Cohort Studies, attitude to health, confounding, Antihypertensive agents, and Cardiovascular medicine and haematology
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Summary Endogenous serum pyrogen from rabbits produced fever in dogs and vice versa. Pyrogenicity of EP in the homologous species was dose related, but this was not the case in the heterologous species. Human serum obtained from patients... more
Summary Endogenous serum pyrogen from rabbits produced fever in dogs and vice versa. Pyrogenicity of EP in the homologous species was dose related, but this was not the case in the heterologous species. Human serum obtained from patients both during fever and after defervescence produced fever in rabbits. These results suggest that pyrogenicity of EP in animals of different species is probably a non-specific phenomenon.
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Page 1. 968 CULTURE OF LYhlPHOCYTES Dennis C. Szymanski, Medical Student Summer Fellowship Grant No. FR-0.5384 from NIH, Division of Research Facilities and Resources. 1. Jeffries, CD, J. Bacteriol. 86, 1358 (1963). 2. Beck, L. V. and... more
Page 1. 968 CULTURE OF LYhlPHOCYTES Dennis C. Szymanski, Medical Student Summer Fellowship Grant No. FR-0.5384 from NIH, Division of Research Facilities and Resources. 1. Jeffries, CD, J. Bacteriol. 86, 1358 (1963). 2. Beck, L. V. and Linkenheimcr, W., Proc. SOC. ...
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Research Interests: Cognitive Science, Epidemiology, Causality, Medicine, Humans, and 15 moreMathematical Sciences, Female, Male, American, Clinical Sciences, Aged, Middle Aged, Educational Status, Neurosciences, Predictive value of tests, Cognition disorders, Neuropsychological Tests, confounding, Medical and Health Sciences, and Percentile
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Background:We have applied latent growth curve (LGC) techniques to the spatial distribution of Alzheimer’s disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study (HAAS). Neurofibrillary tangles... more
Background:We have applied latent growth curve (LGC) techniques to the spatial distribution of Alzheimer’s disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study (HAAS). Neurofibrillary tangles (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. When these were referenced to pre-morbid temporal changes in cognitive performance, it appeared that two populations of NFT might better fit the data. The current analysis explicitly tests the hypothesis that there are two distinct tangle forming processes with different spatial origins and interregional vulnerability gradients.Methods: Age at death adjusted regional NFT counts were modeled as corticotropic and corticofugal growth processes, and regressed onto a corticofugal NP growth process in a structural equation model (SEM) framework, using AMOS. Raw pathology counts were provided by HAAS. Analyses were limited to decedents with "normal" baseline cognition (circa 1991). Results: The final model showed excellent fit (CMIN/ DF 1⁄4 3.6; RMSEA1⁄4 0.029; CFI1⁄4 0.967), and fit better than models of either NFT growth process alone. The Corticotropic Intercept (CTi) in the hippocampus significantly predicted only the Corticotropic Gradient (CTg) into the neocortex. The CTg in the neocortex was significantly associated with the Corticofugal Intercept (CFi) in the same regions and both the "Early" NP intercept in the neocortex (Early NP), and the "Late" NP gradient (Late NP) extending into the hippocampus. The CFi in the neocortex was significantly associated with "Early" NP in the same regions but not "Late" NP in the hippocampus. "Late" NP in the hippocampus were significantly associated only with CFg in the same structures, in a feedback loop. Conclusions: These data suggest that there are two distinct tangle forming processes that sum to produce observed ADpathology at autopsy. Corticofugal tangle formation is associated with corticofugal NP formation, and may precede it. Both corticofugal processesmaybe preceded by corticotropic tangle formation that is not co-localized in space (and presumably time) with cofticofugalNP formation. The corticofugal processesmost likely drive cognitive decline (i.e., via beta amyloid neuro-toxicity) and can be dated relative to cognitive changes in HAAS and /or NP formation, which is imagable.
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Objective While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy... more
Objective While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up.Methods Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72–97 years.Results Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1–4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies.Conclusions The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.
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The interleukin-1 (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that... more
The interleukin-1 (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) and vascular dementia (VaD) may share genetic risk factors. In this study, the frequency of polymorphisms in the genes coding for interleukin (IL)-1alpha, IL-1beta and the IL-1 receptor antagonist (RN) and their genotype associations with late-onset AD and VaD were determined in a Japanese-American cohort of men (n=931) participating in the Honolulu-Asia Aging Study (HAAS). A significant association was found between the IL-1beta (-511) and IL-1RN (+2018) polymorphisms and AD, suggesting that these variants confer an increased risk. Possessing the IL-1beta (-511) T/T genotype was also associated with VaD. There was no difference in the IL-1beta (+3953) frequency among the groups. Our results support the hypothesis that certain genetic variations contained within the IL-1 gene family contribute to the pathogenesis of dementia.
Research Interests: Dementia, Aging, Biology, Medicine, Humans, and 15 moreDisease, Male, Apolipoprotein E, Clinical Sciences, Aged, Longitudinal Studies, Genotype, Asian Continental Ancestry Group, Gene Family, Alzheimer Disease, Neurosciences, Case Control Studies, Interleukin, Gene frequency, and Genetic predisposition to disease
A nested case-control study of 84 incident cases of patients with idiopathic Parkinson&amp;amp;amp;amp;amp;amp;#39;s disease (PD) detected by June 30, 1994 and 336 age-matched control subjects, compared previously-documented intake of... more
A nested case-control study of 84 incident cases of patients with idiopathic Parkinson&amp;amp;amp;amp;amp;amp;#39;s disease (PD) detected by June 30, 1994 and 336 age-matched control subjects, compared previously-documented intake of total dietary vitamin E and of selected vitamin E-containing foods. All study subjects had been followed for 27 to 30 years after diet recording in the 8,006-man Honolulu Heart Study cohort. We determined PD outcomes by periodic cohort re-examination and neurologic testing, private physician reports, examination of O&amp;amp;amp;amp;amp;amp;#39;ahu neurologists&amp;amp;amp;amp;amp;amp;#39; office records, and continual death certificate and hospital discharge diagnosis surveillance. Data on vitamin E intake, obtained from three dietary data sets at the time of cohort enrollment (1965 to 1968), included a food-frequency questionnaire and a 24-hour photograph-assisted dietary recall administered by trained dietitians. Although absence of PD was significantly associated with prior consumption of legumes (adjusted OR = 0.27, 95% CI 0.09 to 0.78), a dietary variable preselected for high vitamin E content, neither food categories nor quartiles nor continuous variables of vitamin E consumption were significantly associated with PD occurrence. Though consistent with prior reports of PD protection afforded by legumes, and with speculation on the possible benefits of dietary or supplemental vitamin E in preventing PD, these preliminary data do not conclusively document a beneficial effect of dietary vitamin E on PD occurrence.
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Altered sleep patterns, including changes in bedtime, sleep latency, total sleep time, and arising time, have been reported to occur with increasing age. We examine self-reported sleep patterns in a geographically-defined population (n =... more
Altered sleep patterns, including changes in bedtime, sleep latency, total sleep time, and arising time, have been reported to occur with increasing age. We examine self-reported sleep patterns in a geographically-defined population (n = 3097) of persons aged 65 years and older. Sleep patterns were characterized according to demographic variables, clinical conditions, and physical, psychological, and social functioning. Sleep latency and total hours of sleep increased with age, and older respondents went to bed earlier. The percentage of respondents who reported feeling rested in the morning decreased with age. Women went to bed later, had longer sleep latency, and fewer hours of sleep than men, and were less likely to report feeling rested than men. Sleep patterns were also related to educational attainment, self-perceived health status, physical functional status, psychotropic drug use, alcohol use, depressive symptoms, life satisfaction, and social and recreational activity level. This population study suggests that sleep problems among the elderly are sometimes associated with treatable health conditions and modifiable behavioral and environmental characteristics.