Clinical dementia is the result of the synergistic interaction between: (1) the lifelong accumulation of brain pathologies, which can be only neurodegenerative or combined additively with vascular pathology, and (2) brain reserve, both... more
Clinical dementia is the result of the synergistic interaction between: (1) the lifelong accumulation of brain pathologies, which can be only neurodegenerative or combined additively with vascular pathology, and (2) brain reserve, both structural and cognitive. These two sets of risk factors are independent of one another, but interact to determine risk; thus it is important to take into account both types when determining individual risk. Over time, different diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) have emerged. We discuss different methods for detecting dementia and AD in diverse populations.
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Study Objectives To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild... more
Study Objectives To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) elderly. Methods Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aβ42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA....
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Zusammenfassung Im Rahmen einer Studie zur Erfassung von Risikofaktoren die möglicherweise zu kardiovaskulären Erkrankungen im späteren Lebensalter führen, wurde eine Gruppe von 14-jährigen Schweizer Schülern und Schülerinnen untersucht.... more
Zusammenfassung Im Rahmen einer Studie zur Erfassung von Risikofaktoren die möglicherweise zu kardiovaskulären Erkrankungen im späteren Lebensalter führen, wurde eine Gruppe von 14-jährigen Schweizer Schülern und Schülerinnen untersucht. Diese Untersuchung erfolgte im Schuljahr 1977/1978 im Rahmen des schulärztlichen Dienstes. Die statistische Verteilung folgender Faktoren wird präsentiert: systolische und diastolische Blutdruckwerte, das Gesamtcholesterol, die Triglyceride, sowie die Lipoproteinfrak tion “HDL” des
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Excluding age, family history of dementia is the strongest risk factor for Alzheimer’s disease (AD). Case–control studies suggest that individuals with a family history of dementia have around a three- to fourfold increased risk compared... more
Excluding age, family history of dementia is the strongest risk factor for Alzheimer’s disease (AD). Case–control studies suggest that individuals with a family history of dementia have around a three- to fourfold increased risk compared to those without such a history. Because parents may die without expressing the disease, the association is best seen among siblings. Twin studies suggest a very high heritability (around 80%) for AD, consistent with inherited genes playing the dominant role in determining risk for this illness. Three genes, accounting for <5% of cases, have been identified in which mutations lead to autosomal dominantly transmitted AD. Apolipoprotein E (APOE), which has three major alleles, is the major susceptibility gene for AD, explaining up to 60% of cases. Autopsy studies suggest that its main effects are on the severity of AD neuropathology. Down syndrome (DS), caused by triplication of chromosome 21, is associated with increased AD neuropathology and expression of AD 25–30 years earlier than in people without this syndrome. AD and DS occur more frequently within families, suggesting a genetic association, possibly mediated by chromosomal nondisjunction in some brain cells.
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Nonaspirin nonsteroidal anti-inflammatory drug (NSAID) usage has been shown to have a protective association with incident AD and dementia in many case-control and cohort studies. Longer durations of use have been found to be associated... more
Nonaspirin nonsteroidal anti-inflammatory drug (NSAID) usage has been shown to have a protective association with incident AD and dementia in many case-control and cohort studies. Longer durations of use have been found to be associated with stronger protective effects. When participants of different ages were examined, the effect was seen in those under 75, but not in persons older than this age. This finding is consistent with a significant association in carriers of the apolipoprotein E-e4 allele but not in noncarriers. An NSAID meta-analysis showed significant protective associations in both case-control (OR =0.75, 95% CI =0.68–0.74) and cohort (RR =0.69, 95% CI =0.56–0.86) studies. RCTs in participants with AD have shown no effect. In addition, a large RCT in cognitively impaired older persons with a family history of dementia showed no association of naproxen or celecoxib usage and incidence of AD. Overall, studies of NSAIDS and AD demonstrate that long-term usage, particularly when begun earlier in life, may reduce the risk for AD. Hormone replacement therapy (HRT) has been extensively studied with respect to AD risk. Studies show that if such therapy is begun within a critical time window around the time of menopause and continued for a relatively short number of years, reductions in the risk of AD are seen in later life. A large RCT (the Women’s Health Initiative Memory Study) demonstrated increased risk for dementia in women taking HRT (either unopposed estrogen or estrogen plus progesterone) initiated after age 65, a finding confirmed by several cohort studies. Continuous use of anticholinergic drugs may disclose an underlying disease process.
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Measurement of diet is difficult, given its wide variation based on geography, racial or ethnic group, culture, income, season, and age. The three common ways to measure diet are food diaries, 24-h dietary recall, and food frequency... more
Measurement of diet is difficult, given its wide variation based on geography, racial or ethnic group, culture, income, season, and age. The three common ways to measure diet are food diaries, 24-h dietary recall, and food frequency questionnaires (FFQs). FFQs based on usual food consumption over weeks or months are the most common method used in epidemiologic studies. From the FFQ and a nutrient database, it is possible to determine the intake of specific nutrients. Studies of these nutrients suggest that high intakes of vitamins C and E, particularly together, may be beneficial in reducing risk for AD. Folate and vitamin B12 reduce the levels of homocysteine, an amino acid that can lead to vascular disease. Low levels of these vitamins have been associated with higher risks for developing AD. Low-serum levels of vitamin D have been found to be associated with increased risk for AD. Considerable data support a protective role for polyphenols, which are very potent antioxidants with anti-inflammatory properties. Common sources of polyphenols include fruit and vegetable juices, tea, red wine, curcumin, coffee, chocolates, olives, nuts, soybeans, and cereals. Soy, common in Asian diets, has beneficial effects on postmenopausal women, but reduces cognition in premenopausal women and promotes brain atrophy in men likely through its effect in reducing human estrogen. Consumption of fish (DHA and EPA) and n-3 fatty acids reduce risk of AD, while consumption of trans- or saturated fats increases this risk. Recent studies have focused on dietary patterns (DP), with positive results reported for the Mediterranean Diet as well as other related diets. Reverse causation is an important problem in studies of diet, because DP are likely to change before dementia is diagnosed.
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Autopsy studies where participants were not selected by dementia status have shown that Alzheimer lesions occur independently of vascular lesions. Several studies provide evidence that these two pathologies interact additively to increase... more
Autopsy studies where participants were not selected by dementia status have shown that Alzheimer lesions occur independently of vascular lesions. Several studies provide evidence that these two pathologies interact additively to increase dementia risk. Risk factors for white matter hyperintensities (WMH) include hypertension, diabetes, smoking, hyperlipidemia, and cardiovascular disease. Severe WMH is a risk factor for dementia. Type 2 diabetes, with a prevalence of about 10% in the United States, increases the risk of AD by about 50%. Mechanisms include modulation of Alzheimer and vascular pathology. In diabetics, atrophy occurs predominantly in regions affected early in AD, suggesting a role for insulin resistance in the production of Alzheimer lesions. Glucose lowering treatment slows the rate of atrophy. Midlife hypertension, and in particular high systolic blood pressure, is a significant risk factor for vascular dementia as well as AD. The effect of hypertension is modified by age, with midlife hypertension a risk factor and hypertension in old age either protective or not a risk factor for AD. Antihypertensive treatment reduces the risk for AD and is associated with less AD pathology at autopsy. High midlife cholesterol increases the risk for AD, perhaps through its effect on beta-amyloid accumulation. Midlife obesity, particularly as measured by sagittal abdominal diameter, increases the risk for AD by a factor of two. In old age, overweight and obesity are protective for AD. This finding is related to progressive weight loss that precedes the onset of AD by as many as 20 years. Population attributable fractions for AD are largest for obesity and high cholesterol, and lowest for hypertension and diabetes, largely based on the prevalence of these conditions at midlife.
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Background Cross-cultural studies of Alzheimer disease (AD) in genetically similar populations have been designed to detect possible environmental risk factors. It may be possible to perform similar analyses on a single population by... more
Background Cross-cultural studies of Alzheimer disease (AD) in genetically similar populations have been designed to detect possible environmental risk factors. It may be possible to perform similar analyses on a single population by examining acculturation, which is the extent to which individuals moving into a host society adapt to changes in lifestyle. Our objective was to determine whether acculturation to Western society was a risk factor for developing AD in an elderly population of Japanese-Americans. Study Design and Methods A cohort of 1,622 dementia-free individuals with baseline acculturation scores was followed for 8 years with biennial cognitive screening assessments using the Cognitive Abilities Screening Instrument. Individuals scoring < 88 were given a full physical and neuropsychological evaluation. Diagnoses of dementia and AD were obtained by consensus agreement using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Item response theory was used to combine 20 questionnaire responses to generate acculturation scores. Scores were divided into quartiles for analysis. Hazard ratios were calculated using the Cox proportional hazards model to determine the risk of AD for participants in high quartiles of acculturation versus those in low quartiles. We adjusted models for cardiovascular disease risk factors and demographic characteristics such as primary language and income. Results In unadjusted models, the relative hazard associated with higher levels of acculturation was 0.6 (95% CI 0.4-0.97). With adjustments for demographic characteristics, the relative hazard associated with higher levels of acculturation was 1.84 (95% CI 0.5-6.6). With further adjustments for vascular disease risk factors and apolipoprotein E genotype, the relative hazard associated with higher levels of acculturation was 1.83 (95% CI 0.4-8.5). Conclusion Japanese-Americans in the highest acculturation group appear to have an increased risk for acquiring AD, though the confidence interval includes the null value. This finding suggests further research to determine a biological rationale.
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Background Cross-cultural studies of Alzheimer disease (AD) in genetically similar populations have been designed to detect possible environmental risk factors. It may be possible to perform similar analyses on a single population by... more
Background Cross-cultural studies of Alzheimer disease (AD) in genetically similar populations have been designed to detect possible environmental risk factors. It may be possible to perform similar analyses on a single population by examining acculturation, which is the extent to which individuals moving into a host society adapt to changes in lifestyle. Our objective was to determine whether acculturation to Western society was a risk factor for developing AD in an elderly population of Japanese-Americans. Study Design and Methods A cohort of 1,622 dementia-free individuals with baseline acculturation scores was followed for 8 years with biennial cognitive screening assessments using the Cognitive Abilities Screening Instrument. Individuals scoring < 88 were given a full physical and neuropsychological evaluation. Diagnoses of dementia and AD were obtained by consensus agreement using criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Item response theory was used to combine 20 questionnaire responses to generate acculturation scores. Scores were divided into quartiles for analysis. Hazard ratios were calculated using the Cox proportional hazards model to determine the risk of AD for participants in high quartiles of acculturation versus those in low quartiles. We adjusted models for cardiovascular disease risk factors and demographic characteristics such as primary language and income. Results In unadjusted models, the relative hazard associated with higher levels of acculturation was 0.6 (95% CI 0.4-0.97). With adjustments for demographic characteristics, the relative hazard associated with higher levels of acculturation was 1.84 (95% CI 0.5-6.6). With further adjustments for vascular disease risk factors and apolipoprotein E genotype, the relative hazard associated with higher levels of acculturation was 1.83 (95% CI 0.4-8.5). Conclusion Japanese-Americans in the highest acculturation group appear to have an increased risk for acquiring AD, though the confidence interval includes the null value. This finding suggests further research to determine a biological rationale.
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IntroductionWe evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle.MethodsParticipants from population‐based samples ≥ 60 years of age (n = 623) were... more
IntroductionWe evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle.MethodsParticipants from population‐based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini‐Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans.ResultsTsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age‐standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia.DiscussionThe prevalence of dementia in this cohort is among the lowest in the world. Widespread i...
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Death certificates in most countries including the United States are poor sources of information to assess the contribution of Alzheimer’s disease (AD) to mortality. Even with the increased attention on AD, this diagnosis is frequently... more
Death certificates in most countries including the United States are poor sources of information to assess the contribution of Alzheimer’s disease (AD) to mortality. Even with the increased attention on AD, this diagnosis is frequently omitted as an underlying or contributing cause of death. In 2010, AD was listed as the sixth cause of death in the United States with 83,494 deaths. It is important to note that this refers to AD as an underlying cause of death, not a contributing cause. Estimates from cohort studies suggest that AD may contribute to the mortality of 600,000 Americans annually. AD has been shown to be associated with increased mortality in several studies, reducing life expectancy among both men and women by 1–20 years depending on age. Earlier onset AD is associated with much larger decreases in life expectancy compared to later-onset disease. Given the reduction in mortality from competing causes, such as heart disease and stroke, AD can be expected to account for a growing percentage of deaths in the next several decades.
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Dementia is an umbrella term that refers to an acquired loss of intellectual function that features a disturbance in memory and impairment in function in at least one other domain, such as language, executive functioning, or visuospatial... more
Dementia is an umbrella term that refers to an acquired loss of intellectual function that features a disturbance in memory and impairment in function in at least one other domain, such as language, executive functioning, or visuospatial ability. Although most dementias are progressive, a few are reversible, such as dementia due to B 12 deficiency. Alzheimer’s disease (AD) usually presents with impairments in short-term memory and progresses through several stages to total dependence in all activities of daily living. Stages of this illness can be described using the Clinical Dementia Rating Scale and Global Deterioration Scale. The most frequently used criteria for dementia in epidemiologic studies are the DSM and ICD criteria, which have evolved over the past 40 years. Classification of subtypes of dementia is usually done with the NINCDS-ADRDA criteria for AD and the NINDS-AIREN criteria for vascular dementia (VaD). Early stages of AD and VaD are defined by amnestic mild cognitive impairment and vascular cognitive impairment, for which criteria have been developed.
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In this book, our target is prevention of clinical AD. There are two ways to prevent this condition: by giving interventions that slow the underlying pathologic process, and by maintaining or growing reserve in order to tolerate AD... more
In this book, our target is prevention of clinical AD. There are two ways to prevent this condition: by giving interventions that slow the underlying pathologic process, and by maintaining or growing reserve in order to tolerate AD lesions without becoming demented. Several large clinical trials are in progress, most aimed at evaluating whether immunization with antibodies against Aβ in people who are at high risk but not demented reduces the incidence or biomarker profile of AD. The earliest findings from these trials will be available in 2017. Nonpharmacologic therapies, including diet, and physical and mental exercise also may reduce the levels of Aβ, but more human studies are needed to determine whether this is occurring. A second approach to AD prevention is implementation of interventions based on modifiable risk factors. An NIH State-of-the Science statement published in 2010 concluded that there was insufficient evidence to support the association of any modifiable risk factor with cognitive decline or AD. However, the analyses on which this statement was based had numerous problems, including the focus on cohort studies in which there was a strong possibility of underestimation of relative risk. Three large trials are in progress in Europe in which multimodal interventions, including diet, physical and mental exercise, social interaction, and reduction in vascular risk factors, are being assessed. Risk indices for preclinical detection of AD appear to work best close in time to dementia onset, but midlife indices can offer good predictive accuracy. The development of more comprehensive indices that incorporate markers and risk factors for Alzheimer and vascular pathology as well as measures of reserve are needed.
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Early case-control studies showed a protective effect of smoking on the risk for AD. In addition to survival bias, this finding was likely related to the design of these studies, which excluded individuals with evidence of cerebrovascular... more
Early case-control studies showed a protective effect of smoking on the risk for AD. In addition to survival bias, this finding was likely related to the design of these studies, which excluded individuals with evidence of cerebrovascular disease from the cases, but not from the controls. Cohort studies, which identified incident Alzheimer cases regardless of the presence of cerebrovascular disease, have shown the opposite association, increased risk for incident AD with smoking. This association was stronger in men, in those without a family history of dementia and in those who did not carry an APOE-e4 allele. The risk for AD in relation to smoking is modified by age, with younger people showing an increased risk and older people a decreased risk. A likely explanation is that smokers susceptible to AD do not survive to old age. The association of smoking and increased risk for AD appears to be restricted to current rather than former smoking, consistent with the data on stroke risk. Studies of alcohol consumption suggest that low to moderate intake of alcohol is inversely associated with AD risk, with both teetotalers and heavy drinkers incurring higher risks. Many studies have shown that wine consumption is inversely associated with AD risk, likely due to the high levels of polyphenols. Multiple biologic mechanisms may underlie alcohol effects on incident AD, including the cardiovascular and cerebrovascular benefits from low to moderate consumption, brain atrophy from higher consumption, and modulation of amyloidosis. Associations between alcohol and AD could represent a true effect or several biases, including survival, healthy-person effect, reverse causation and confounding.
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The initial findings of studies linking social engagement with risk of dementia showed that living alone, living without close ties, or living as a single person increased dementia risk. The principal methodological problem with many... more
The initial findings of studies linking social engagement with risk of dementia showed that living alone, living without close ties, or living as a single person increased dementia risk. The principal methodological problem with many cohort studies of this exposure is that of reverse causation, withdrawal from social ties with impending cognitive impairment. Findings from cohort studies highlight the importance of quality of social interactions versus quantity. In most studies, marriage or cohabitation appears to reduce the risk of dementia, particularly in men. This appears to be particularly important for men who lost a partner through widowhood. Data from the HAAS, where information on social engagement was obtained during midlife and during late life close to time of onset of dementia showed that midlife social engagement was not related to dementia risk, while late life social engagement was. This finding provides support for the view that the association is due to reverse causation. Studies of loneliness point to the importance of subjective perceptions of social connections rather than the connections themselves in the association with dementia. Data from one study showed that more socially engaged people had greater brain volumes. The size of the social network was found to be related to cognition in persons with similar levels of AD neuropathology at autopsy. It is difficult to determine the role of social engagement in multimodal intervention studies in which it is one of many components. In summary, findings suggest that subject perceptions of social disconnection appear to be related more strongly to dementia risk than objective measures such as social network size.
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No abstract is available. To read the body of this article, please view the Full Text online. ... © 2009 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. ... Visit SciVerse ScienceDirect to see if you have... more
No abstract is available. To read the body of this article, please view the Full Text online. ... © 2009 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved. ... Visit SciVerse ScienceDirect to see if you have access via your institution. ... Advertisements on this site ...
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No abstract is available. To read the body of this article, please view the Full Text online. ... © 2009 The Alzheimer&amp;amp;#x27;s Association. Published by Elsevier Inc. All rights reserved. ... Visit SciVerse ScienceDirect to see... more
No abstract is available. To read the body of this article, please view the Full Text online. ... © 2009 The Alzheimer&amp;amp;#x27;s Association. Published by Elsevier Inc. All rights reserved. ... Visit SciVerse ScienceDirect to see if you have access via your institution. ... Advertisements on this site ...
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aim of this study was to analyze the effect of a psycho educational programme focused on the modification of the negative emotions and the dysfunctional thought’s within a Spanish Alzheimer’ disease patient’s caregiver’s. Methods: The... more
aim of this study was to analyze the effect of a psycho educational programme focused on the modification of the negative emotions and the dysfunctional thought’s within a Spanish Alzheimer’ disease patient’s caregiver’s. Methods: The sample of this study consisted of 51 spanish community dwelling Alzheimer’s patient’s informal caregivers: they were distributed into two treatment conditions, the experimental group (n1⁄420), and the control group (n1⁄431). All the participants were evaluated before and after the intervention through the application of different standardized measurement tools: depression (CES-D Scale, Radloff, 1977), perceived stress (Perceived Stress Scale, Cohen, Karmarck & Mermelstein, 1983), dysfunctional thoughts (Losada, Montorio, Izal & Márquez-González, 2006), negative and positive affect (Positive and Negative Affect Schedule, Watson, Clark, & Tellegen, 1988), burden (Zarit, Reever & Bach-Peterson, 1980), satisfaction with care (Lawton, Kleban, Moss, Rovine & Glicksman, 1989), and sociodemographic measures (age, sex, amount of hours they usually sleep, etc.). For the measurement of the perceived health two questions were created in order to know the subjective perception about their health status. Results: After the psycho educational programme, the participants in the experimental group showed statistically significant differences in perceived health status [t1⁄4 -2.50; p< .05], emotional balance [t1⁄4 -2.89; p< .01] and satisfaction with care [t1⁄4 4.47; p< .001], depression [t1⁄4 4.16; p< .001], reaction to behavioural problems [t1⁄4 2.77; p< .01], burden [t1⁄4 3.37; p< .01], perceived stress [t1⁄4 2.55; p< .05] and negative affect [t1⁄4 2.60; p< .05.]. Results show that participants in the experimental group have a better perceived health status, emotional balance and are more satisfied with the care giving process. On the other hand show less depressive mood, burden related with patient’s behavioural problems, perceived stress and negative affect. Conclusions: Results in this study indicate that a psychosocial intervention can be effective in the improvement of certain psychological and emotional variables of the informal caregiver.
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Effective prevention of Alzheimer’s disease (AD) will require identification of people at risk of this illness, preferably long before the first clinical symptoms. Although imaging and analysis of CSF proteins can identify individuals who... more
Effective prevention of Alzheimer’s disease (AD) will require identification of people at risk of this illness, preferably long before the first clinical symptoms. Although imaging and analysis of CSF proteins can identify individuals who will get this illness up to 15 years prior to its onset, these modalities are unlikely to be useful in populations, where the search for noninvasive, cost-effective markers is underway. Two major types of risk factors for AD can be identified, those for its pathology and those for its clinical expression. A third type of risk factor is a marker for the underlying disease. In addition to finding pharmacologic interventions that slow the pathogenesis of the disease, we need to focus on modifiable risk factors that influence its expression. Observational studies have included case–control studies that offered the first clues to risk factors and cohort studies. Both of these types of studies have associated methodological problems and the accepted hierarchy of study designs with randomized controlled trials at the top followed by cohort studies and then by case–control studies needs to be reconsidered in studies of Alzheimer’s disease.
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Standardized definitions of what constitutes a case of AD or dementia are essential to guard against misclassification of the outcome and consequent misestimation of risk and odds ratios. Well-designed studies often carry out a... more
Standardized definitions of what constitutes a case of AD or dementia are essential to guard against misclassification of the outcome and consequent misestimation of risk and odds ratios. Well-designed studies often carry out a rediagnosis of cases using standardized criteria and methods. Passive case-finding from medical records is acceptable if enough information is available to confirm that diagnoses were made in a uniform way. Most cohort studies have used a two-phase design, screening for potential cases using a brief global cognitive measure followed by detailed clinical evaluation of suspects. Better estimates of prevalence and incidence can be obtained by evaluating samples of individuals who score well on the screening test in addition to all of those who score poorly. It is generally easier to identify prevalent than incident cases, because the former usually strongly satisfy all criteria for dementia or AD, whereas the latter may satisfy these criteria marginally. A large, national cohort study in the United States is needed that would examine risk factors for AD incidence within multiple racial/ethnic and cultural groups using a standardized methodological framework.
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Risk factors for disease can be either causal risk factors or markers of underlying pathology. A key question is whether a potential marker tracks pathology. An example of a risk factor that is likely both a marker and a causal risk... more
Risk factors for disease can be either causal risk factors or markers of underlying pathology. A key question is whether a potential marker tracks pathology. An example of a risk factor that is likely both a marker and a causal risk factor is depression. Several meta-analyses as well as individual studies have shown that depression earlier in life is associated with both MCI and AD. For example, a meta-analysis published in 2006 showed a pooled OR of 2.03 (95% CI=1.73–2.38) for case-control studies and a pooled HR of 1.90 (95% CI=1.55–2.33) for cohort studies. Depression is related to reductions in volume in several brain regions, including the hippocampus. Possible mechanisms include the overproduction of glucocorticoids as a result of stress. PAFs for depression range from 8% to 11%. Prodromal expression of depression prior to the onset of AD is likely to be a marker for underlying disease progression. Loss or decline in olfaction is a marker for underlying AD pathology and is evident in first-degree relatives of AD patients who have an increased risk of this illness. Associations with olfaction have been seen with hippocampal volume as well as thickness of the entorhinal cortex. Change in olfaction clearly precedes MCI and therefore is a useful early marker for prediction of incident AD. Subjective memory complaints (SMC), another marker for AD, occur at about the same time or before the first objective findings of memory loss. They are associated with the severity of both plaques and tangles in older persons without dementia. Studies have shown that stronger associations between SMC and incident dementia are evident in those with higher education, higher IQ, female sex, higher baseline cognitive scores and younger age.
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Biomarkers are measurable indicators of the presence or severity of underlying disease pathology. Ideal biomarkers for detection of preclinical disease should have high sensitivity and specificity long before the first symptoms appear.... more
Biomarkers are measurable indicators of the presence or severity of underlying disease pathology. Ideal biomarkers for detection of preclinical disease should have high sensitivity and specificity long before the first symptoms appear. Present markers that fulfill these requirements include cerebrospinal fluid (CSF) assays of Aβ 1–42 and tau, PET scans for detecting aggregated Aβ, and atrophy of key brain regions affected early in Alzheimer’s. CSF Aβ 1–42 , total, and p -tau as well as the ratio of tau to Aβ 1–42 provide sensitive and specific identification of pathology up to 15 years prior to Alzheimer’s disease (AD) diagnosis. Plasma Aβ and tau are more unreliable in predicting AD. However, as part of a larger marker panel, they could be helpful in predicting future AD in studies in which CSF and PET-scan studies are not practical. Hippocampal volume has been shown to be strongly related to the severity of AD neuropathology and is as sensitive and specific as CSF markers for future prediction of AD. Reliable differences in hippocampal volume are apparent 15 years before AD diagnosis. Fibrillary amyloid PET has high sensitivity and specificity for neuritic plaques and is useful for detection of AD 15 years prior to diagnosis. However, the development of specific tracers for Aβ oligomers could lead to earlier detection. PET imaging of pathologic tau, while still under development, could be useful in early identification of individuals at risk for AD. Fluorodeoxyglucose PET reflects synaptic activity and appears to change around 10 years prior to diagnosis. Despite the general consensus that impairment in delayed memory is the first cognitive sign of AD, longitudinal studies show impairments in verbal fluency and other tests much earlier. Because of low specificity, cognitive measures by themselves are unlikely to provide reliable prediction in individuals. Combinations of biomarkers, especially combinations that include APOE, are likely to provide the best predictors of risk in individuals.
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Similar to prevalence, incidence rates for AD and dementia double every 5 years. Studies of MCI incidence and transitions to dementia, death, and normal cognition suggest that many MCI patients revert to normal cognition, often before... more
Similar to prevalence, incidence rates for AD and dementia double every 5 years. Studies of MCI incidence and transitions to dementia, death, and normal cognition suggest that many MCI patients revert to normal cognition, often before transitioning again to MCI and then to dementia. Data from autopsy studies show that AD pathology is likely to decrease at ages above 90, but that incidence of dementia continues to rise. Comparisons of incidence rates of AD in women and men have produced mixed findings, with women living to age 85 and beyond likely at somewhat higher risk than men of this age. Most studies have found higher rates of AD and dementia in African-Americans as compared to Caucasians. Incidence rates for dementia are fairly comparable in middle- and high-income countries but may be lower in some disadvantaged populations. AD incidence appears to have been decreasing for the past three decades, perhaps due to the increases in education, brain size, and other protective factors. Whether this trend will continue with the increase in incidence of obesity and diabetes, risk factors for AD, will not be clear for several decades.
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BackgroundDeterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation... more
BackgroundDeterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC).ObjectiveTo test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E(APOE).MethodsThis study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2x2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized.ResultsAmong those aged >65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p=0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged >65 years old (p values=0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e. cg13496662 and cg06750524) in APOE (p for indirect effect=0.05).ConclusionsOur findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer’s disease.
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Alzheimer's Disease: Lifecourse Perspectives on Risk Reduction summarizes the growing body of knowledge on the distribution and causes of Alzheimer's disease (AD) in human populations, providing the reader with knowledge on how we... more
Alzheimer's Disease: Lifecourse Perspectives on Risk Reduction summarizes the growing body of knowledge on the distribution and causes of Alzheimer's disease (AD) in human populations, providing the reader with knowledge on how we define the disease and what its risk and protective factors are in the context of a life-course approach. At the conclusion of the book, the reader will understand why Alzheimer's disease likely begins at conception, then progresses through early-life and adult risk factors that ultimately impact the balance between pathologic insults in the brain and the ability of the brain to modify disease symptoms. In contrast to edited volumes that may have little cohesion, this book focuses on an integrated life-course approach to the epidemiology of dementia, in particular, Alzheimer's disease. Reviews the current science surrounding Alzheimer's diseaseProvides a primer of foundational knowledge on the disease's epidemiology and biostatisticsUtilizes a life-course approach, providing a novel and integrated view of the evolution of this illness from genes to brain reserveUses the ?threshold model'?a theory first described by Dr. Mortimer and widely accepted today?which incorporates the idea of risk factors for the pathology and expression of the disease Proposes that improving brain health through modifiable behaviors can delay disease onset until a later ageExamines the future of prevention of Alzheimer's disease, a subject of great current interest
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BackgroundSubstantial variations in the prevalence of mild cognitive impairment (MCI) have been reported, although mostly in Western countries. Less is known about MCI in the Chinese population.MethodsWe clinically and... more
BackgroundSubstantial variations in the prevalence of mild cognitive impairment (MCI) have been reported, although mostly in Western countries. Less is known about MCI in the Chinese population.MethodsWe clinically and neuropsychologically evaluated 3141 community residents ≥60 years of age. Diagnoses of MCI and its subtypes were made using standard criteria via consensus diagnosis.ResultsAmong 2985 nondemented individuals, 601 were diagnosed with MCI, resulting in a prevalence of 20.1% for total MCI, 13.2% for amnestic MCI (aMCI), and 7.0% for non‐amnestic MCI (naMCI). The proportions of MCI subtypes were: aMCI single domain (SD), 38.9%; aMCI multiple domains (MD), 26.5%; naMCI‐SD, 25.0%; and naMCI‐MD, 9.6%. The prevalence of aMCI‐MD increased rapidly with age in women APOE ε4 carriers (from 60 to 69 years to ≥80 years, 3.1%–33.3%, P &lt; .001).ConclusionsOur findings suggest that 20% of Chinese elderly are affected by MCI. Prospective studies in China are needed to examine progression to dementia and related risk factors.
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cerebellum reference) to generate Centiloids. The relationship between Centiloids versus CERAD and Thal stages was investigated. Finally, we assessed the performance of two a priori thresholds previously introduced by our group (liberal... more
cerebellum reference) to generate Centiloids. The relationship between Centiloids versus CERAD and Thal stages was investigated. Finally, we assessed the performance of two a priori thresholds previously introduced by our group (liberal –SUVR 1.21 1⁄4 7.47 Centiloids; conservative –SUVR 1.40 1⁄4 27.48 Centiloids), and further derived an empirical threshold by performing ROC analysis of the current dataset, using CERAD moderate-frequent plaques as the standard of truth. Results: CERAD none-sparse patients had a mean of -4.8566.88 Centiloids; the moderate-frequent group had 66.02650.45 Centiloids (t-test, p<0.001). The ROC analysis identified 9.50 Centiloids as the optimal threshold with 0.89 sensitivity (95% CI:0.71-0.97), 1.00 specificity (0.86 – 1.00); AUC 0.91 (0.808-1.000) (Figure 1). The a priori liberal threshold had identical sensitivity and specificity as the ROC-derived threshold. These thresholds also distinguished between Thal phases 0-2 and 3-5 (Figure 2). The a priori conservative threshold had sensitivity of 0.68 (0.48-0.83) and specificity of 1.00 (0.86-1.0). Conclusions: The a priori liberal threshold (7.47 Centiloids) and the ROCderived threshold (9.50 Centiloids) showed excellent sensitivity/ specificity, and could be considered for detection of early amyloid signal. By the time of AAIC we anticipate processing at least 100 additional cases currently being provided by multiple sites in order to validate these preliminary results.
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Introduction: An important index of brain reserve is the maximal attained brain size, which can be estimated by measuring the head circumference (HC). We investigated the association of HC and education with incident dementia in a... more
Introduction: An important index of brain reserve is the maximal attained brain size, which can be estimated by measuring the head circumference (HC). We investigated the association of HC and education with incident dementia in a population-based study of Chinese older adults. Methods: We conducted a prospective follow-up study of 1,659 non-demented participants with a mean age of 71.5 years. Characteristics and anthropometry of the participants were collected at baseline. Consensus diagnoses for dementia were made using DSM-IV criteria based on functional, neurological, and neuropsychological assessments. Results: We identified 168 new-onset dementia cases after a mean of 5.2 years of follow-up. Participants with smaller HC combined with low educational attainment had a significantly higher risk of incident dementia than those with larger HC who had completed more than 12 years of education (adjusted hazard ratio 4.48, 95% CI 2.47–8.12). Discussion/Conclusion: Our results suggest ...
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Ongoing demographic trends will lead to a huge increase in the prevalence of dementia worldwide in the next 35 years if interventions to reduce its incidence are not implemented. There are many challenges to comparing prevalence rates of... more
Ongoing demographic trends will lead to a huge increase in the prevalence of dementia worldwide in the next 35 years if interventions to reduce its incidence are not implemented. There are many challenges to comparing prevalence rates of Alzheimer’s disease and dementia across countries, including differences in cultural interpretations of memory loss in older people, lifestyle factors that reduce motivation for seeking medical attention for dementia, and application of case-finding methods. Differences in age distributions and mortality rates between countries as well as differences in risk factors, such as genes and education, also are important to consider. Despite these differences, an increase in prevalence with age characterized by a doubling in rate every 5 years has been universally observed. Some data also support an increased prevalence in women compared to men, especially in very old age. In the United States, African-Americans are believed to have twice the prevalence of whites, and Hispanics one-and-a-half times the prevalence of whites. This difference may be due in part to the higher prevalence of vascular diseases and lower levels of education in minority populations.
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The ability of people to maintain a high level of cognitive function in the presence of substantial Alzheimer pathology is often attributed to brain or cognitive reserve. An early model proposed that dementia occurred when a critical... more
The ability of people to maintain a high level of cognitive function in the presence of substantial Alzheimer pathology is often attributed to brain or cognitive reserve. An early model proposed that dementia occurred when a critical number of Alzheimer lesions or brain softening secondary to infarcts was reached. Reformulation of this model to consider the amount of functional brain reserve instead of the amount of pathology permitted differences in the initial level of brain reserve to affect the risk of dementia. Measurement of the amount of reserve has been an important challenge, with most estimates based on education, literacy, IQ, occupational characteristics, brain volume, or head circumference. Studies have shown that low education is a strong risk factor for dementia and AD. An additional risk factor is maximum brain size, individuals with larger brains having a lower risk of AD. Recent studies have suggested that the amount of reserve is likely as important as the severity of Alzheimer lesions in predicting dementia.