Associations of reproductive factors and exogenous estrogens with global and domain-specific cognition in later life.

INTRODUCTION: Few studies have comprehensively examined the impact of reproductive factors (i.e., reproductive window, parity, hormonal contraception [HC], and menopausal hormone therapy [MHT]) on global and domain-specific cognition in later life. METHODS: We studied a population-based sample of 2458 women (median age 74.2 years) residing in Olmsted County, Minnesota; participants underwent a clinical evaluation and comprehensive cognitive testing. RESULTS: The length of a woman's reproductive window was not associated with cognition. Higher parity was associated with greater cognitive decline in all domains. Ever HC use was associated with less decline in all domains. Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial; results were driven by women who initiated MHT 5 or more years after menopause. Additional adjustments for APOE and vascular-related covariates did not attenuate the results. DISCUSSION: Multiple reproductive risk factors are associated with cognitive decline in later life. HIGHLIGHTS: The length of a woman's reproductive window was not associated with cognition longitudinally. Greater parity was associated with greater cognitive decline longitudinally. Ever HC use was associated with less decline in global cognition and all domain-specific z-scores longitudinally (all p < 0.01). Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial longitudinally (all p < 0.01). The greatest cognitive decline was among women who initiated MHT more than 5 years after menopause.

Longitudinal associations of reproductive factors and exogeneous estrogens with neuroimaging biomarkers of Alzheimer's disease and cerebrovascular disease.

INTRODUCTION: Female-specific reproductive factors and exogeneous estrogen use are associated with cognition in later life. However, the underlying mechanisms are not understood. The present study aimed to investigate the effect of reproductive factors on neuroimaging biomarkers of Alzheimer's disease (AD) and cerebrovascular pathologies. METHODS: We evaluated 389 females (median age of 71.7 years) enrolled in the Mayo Clinic Study of Aging with reproductive history data and longitudinal magnetic resonance imaging (MRI) scans. We used linear mixed effect models to examine the associations between reproductive factors and changes in neuroimaging measures. RESULTS: Ever hormonal contraception (HC) use was longitudinally associated with higher fractional anisotropy across the corpus callosum, lower white matter hyperintensity (WMH) volume, and greater cortical thickness in an AD meta-region of interest (ROI). The initiation of menopausal hormone therapy (MHT) > 5 years post menopause was associated with higher WMH volume. DISCUSSION: HC use and initiation of MHT >5 years post menopause were generally associated with neuroimaging biomarkers of cerebrovascular pathologies. HIGHLIGHTS: Hormonal contraception use was associated with better brain white matter (WM) integrity. Initiation of menopausal hormone therapy >5 years post menopause was associated with worsening brain WM integrity. Hormonal contraception use was associated with greater cortical thickness. Ages at menarche and menopause and number of pregnancies were not associated with imaging measures. There were few associations between reproductive factors or exogenous estrogens and amyloid or tau PET.

Premenopausal bilateral oophorectomy and brain white matter brain integrity in later-life.

INTRODUCTION: Premenopausal bilateral oophorectomy (PBO) is associated with later-life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity. METHODS: Female participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40-45 years; 39 with PBO 46-49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype. RESULTS: Females with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto-occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity. DISCUSSION: Females who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later-life. These results are important for females considering PBO for noncancerous conditions. HIGHLIGHTS: Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents. Females with PBO < 40 years had higher MD in many regions versus referents. Adjusting for estrogen replacement therapy use did not attenuate results. Females with PBO 45-49 years also had some white matter changes versus referents.

Smoking, early menopause and multiple sclerosis disease course.

Smoking is associated with an increased risk of multiple sclerosis (MS), and smoking and early menopause are related to poor outcomes in MS. Smoking is also associated with early menopause. To explore this intricate relationship between smoking status, age at menopause and disease course in MS, 137 women with MS and 396 age-matched controls were included in this case-control study. Age at menopause (median 49.0 vs. 50.0 years; p = 0.79) and smoking status (40.3% vs. 47.6%; p = 0.15) were similar among MS and control women. Relapsing MS onset was earlier in ever-smoker women with early menopause compared to the rest of the women (median 30.4 vs. 37.0 years; p = 0.02) and also compared to ever-smoker women with normal age at menopause (median 30.4 vs. 41.0 years; p = 0.008) and never-smoker women with early menopause (median 30.4 vs. 41.5 years; p = 0.004). Progressive MS onset was also earlier in ever-smoker women with early menopause compared to ever-smoker women with normal age at menopause (median 41.1 vs. 49.4 years; p = 0.05) and never-smoker women with early menopause (median 41.1 vs. 50.1 years; p = 0.12). Our results suggest that smoking and menopause associate with MS disease course, including the onset of relapsing and progressive MS in women.

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.

Risk of de novo cancer after premenopausal bilateral oophorectomy.

BACKGROUND: Hysterectomy is one of the most frequent gynecologic surgeries in the United States. Women undergoing hysterectomy are commonly offered bilateral oophorectomy for ovarian and breast cancer prevention. Although bilateral oophorectomy may dramatically reduce the risk of gynecologic cancers, some studies suggested that bilateral oophorectomy may be associated with an increased risk of other types of cancer, such as lung cancer and colorectal cancer. However, the results are conflicting. OBJECTIVE: To study the association between bilateral oophorectomy and the risk of subsequent cancer of any type. STUDY DESIGN: This population-based cohort study included all premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication before the age of 50, between January 1, 1988 and December 31, 2007 in Olmsted County, Minnesota, and a random sample of age-matched (±1 year) referent women who did not undergo bilateral oophorectomy. Women with cancer before oophorectomy (or index date) or within 6 months after the index date were excluded. Time-to-event analyses were performed to assess the risk of de novo cancer. Cancer diagnosis and type were confirmed using medical record review. RESULTS: Over a median follow-up of 18 years, the risk of any cancer did not significantly differ between the 1562 women who underwent bilateral oophorectomy before natural menopause and the 1610 referent women (adjusted hazard ratio, 0.82; 95% confidence interval, 0.66-1.03). However, women who underwent bilateral oophorectomy had a decreased risk of gynecologic cancers (adjusted hazard ratio, 0.15; 95% confidence interval, 0.06-0.34) but not of nongynecologic cancers (adjusted hazard ratio, 0.99; 95% confidence interval, 0.78-1.26). In particular, the risk of breast cancer, gastrointestinal cancer, and lung cancer did not differ between these 2 cohorts. Use of estrogen therapy through the age of 50 years in women who underwent bilateral oophorectomy did not modify the results. CONCLUSION: Women who underwent bilateral oophorectomy before menopause have a reduced risk of gynecologic cancer but not of other types of cancer including breast cancer. Women at average risk of ovarian cancer should not consider bilateral oophorectomy for the prevention of breast cancer or other nongynecologic cancers.

Identifying Information Gaps in Electronic Health Records by Using Natural Language Processing: Gynecologic Surgery History Identification.

BACKGROUND: Electronic health records (EHRs) are a rich source of longitudinal patient data. However, missing information due to clinical care that predated the implementation of EHR system(s) or care that occurred at different medical institutions impedes complete ascertainment of a patient's medical history. OBJECTIVE: This study aimed to investigate information discrepancies and to quantify information gaps by comparing the gynecological surgical history extracted from an EHR of a single institution by using natural language processing (NLP) techniques with the manually curated surgical history information through chart review of records from multiple independent regional health care institutions. METHODS: To facilitate high-throughput evaluation, we developed a rule-based NLP algorithm to detect gynecological surgery history from the unstructured narrative of the Mayo Clinic EHR. These results were compared to a gold standard cohort of 3870 women with gynecological surgery status adjudicated using the Rochester Epidemiology Project medical records-linkage system. We quantified and characterized the information gaps observed that led to misclassification of the surgical status. RESULTS: The NLP algorithm achieved precision of 0.85, recall of 0.82, and F1-score of 0.83 in the test set (n=265) relative to outcomes abstracted from the Mayo EHR. This performance attenuated when directly compared to the gold standard (precision 0.79, recall 0.76, and F1-score 0.76), with the majority of misclassifications being false negatives in nature. We then applied the algorithm to the remaining patients (n=3340) and identified 2 types of information gaps through error analysis. First, 6% (199/3340) of women in this study had no recorded surgery information or partial information in the EHR. Second, 4.3% (144/3340) of women had inconsistent or inaccurate information within the clinical narrative owing to misinterpreted information, erroneous "copy and paste," or incorrect information provided by patients. Additionally, the NLP algorithm misclassified the surgery status of 3.6% (121/3340) of women. CONCLUSIONS: Although NLP techniques were able to adequately recreate the gynecologic surgical status from the clinical narrative, missing or inaccurately reported and recorded information resulted in much of the misclassification observed. Therefore, alternative approaches to collect or curate surgical history are needed.

Correction to: Neighborhood socioeconomic disadvantage is associated with multimorbidity in a geographically-defined community.

An amendment to this paper has been published and can be accessed via the original article.

Neighborhood socioeconomic disadvantage is associated with multimorbidity in a geographically-defined community.

BACKGROUND: Persons with low socioeconomic status may be disproportionately at risk for multimorbidity. METHODS: Adults aged ≥20 years on 4/1/2015 from 7 counties in Minnesota were identified using the Rochester Epidemiology Project (population-based sample). A composite measure of neighborhood socioeconomic disadvantage, the area deprivation index (ADI), was estimated at the census block group level (n = 251). The prevalence of 21 chronic conditions was obtained to calculate the proportion of persons with multimorbidity (≥2 chronic conditions) and severe multimorbidity (≥5 chronic conditions). Hierarchical logistic regression was used to estimate the association of ADI with multimorbidity and severe multimorbidity using odds ratios (OR). RESULTS: Among 198,941 persons (46.7% male, 30.6% aged ≥60 years), the age- and sex-standardized (to the United States 2010 census) median prevalence (Q1, Q3) was 23.4% (21.3%, 25.9%) for multimorbidity and 4.8% (4.0%, 5.7%) for severe multimorbidity. Compared with persons in the lowest quintile of ADI, persons in the highest quintile had a 50% increased risk of multimorbidity (OR 1.50, 95% CI 1.39-1.62) and a 67% increased risk of severe multimorbidity (OR 1.67, 95% CI 1.51-1.86) after adjusting for age, sex, race, and ethnicity. Associations were stronger after further adjustment for individual level of education; persons in the highest quintile had a 78% increased risk of multimorbidity (OR 1.78, 95% CI 1.62-1.96) and a 92% increased risk of severe multimorbidity (OR 1.92, 95% CI 1.72-2.13). There was evidence of interactions between ADI and age, between ADI and sex, and between ADI and education. After age 70 years, no difference in the risk of multimorbidity was observed across quintiles of ADI. The pattern of increasing multimorbidity with increasing ADI was more pronounced in women. Finally, there was less variability across quintiles of ADI for the most highly educated group. CONCLUSIONS: Higher ADI was associated with increased risk of multimorbidity, and the associations were strengthened after adjustment for individual level of education, suggesting that neighborhood context plays a role in health above and beyond individual measures of socioeconomic status. Furthermore, associations were more pronounced in younger persons and women, highlighting the importance of interventions to prevent chronic conditions in younger women, in particular.

Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging.

Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia.

Importance: A National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers. Objective: To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information. Design, Setting, and Participants: Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018. Exposures: Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles. Main Outcomes and Measures: Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only. Results: Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier. Conclusions and Relevance: Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.

Parkinson disease with and without Dementia: A prevalence study and future projections.

BACKGROUND: Limited population-based information is available on the co-occurrence of dementia and PD. However, projecting the prevalence of PD with and without dementia during the next 50 years is crucial for planning public-health and patient-care initiatives. OBJECTIVES: The objective of this study was to project the prevalence of PD with and without dementia in the United States by 2060. METHODS: We used the Rochester Epidemiology Project medical records-linkage system to identify all persons with PD with or without dementia residing in Olmsted County, Minnesota, on January 1, 2006. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of PD. We calculated the age- and sex-specific prevalence of PD with and without dementia and projected U.S. prevalence through 2060. RESULTS: We identified 296 persons with PD with and without dementia on the prevalence date (187 men, 109 women); the overall prevalence increased with age from 0.01% (30-39 years) to 2.83% (≥90 years). The prevalence of PD without dementia increased with age from 0.01% (30-39 years) to 1.25% (≥90 years). The prevalence of PD with dementia increased with age from 0.10% (60-69 years) to 1.59% (≥90 years). The prevalence was higher in men than in women for all subtypes and all age groups. We project by 2060 an approximate doubling of the number of persons with PD without dementia and a tripling of the number of persons with PD with dementia in the United States. CONCLUSIONS: The prevalence of PD with and without dementia increases with age and is higher in men than women. We project that the number of persons with PD in the United States will increase substantially by 2060. © 2018 International Parkinson and Movement Disorder Society.

Prevalence of and indications for antipsychotic use in Parkinson's disease.

BACKGROUND: The prevalence of patients with PD taking antipsychotics is unknown. OBJECTIVE: To measure the prevalence of patients with PD taking antipsychotics. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to study the use of antipsychotic medication in all persons with Parkinson disease in Olmsted County, Minnesota on 1 January 2006. RESULTS: There were 296 patients with PD in Olmsted County on 1 January 2006. The overall prevalence of antipsychotic use was 9.8% (29 of 296); 95.5% (28 of 29) of the patients had dementia when initiating antipsychotics. The most frequent indication (71.4%; 20 of 28) was psychosis or behavior threatening to the patient or others. CONCLUSIONS: The prevalence of antipsychotic use in patients with PD is lower than expected from previously reported cumulative incidences. Dementia is highly prevalent in those starting antipsychotics. Most of the patients on antipsychotics had a reasonable risk-benefit ratio for taking them. © 2017 International Parkinson and Movement Disorder Society.

Rochester Epidemiology Project Data Exploration Portal.

INTRODUCTION: The goal of this project was to develop an interactive, web-based tool to explore patterns of prevalence and co-occurrence of diseases using data from the expanded Rochester Epidemiology Project (E-REP) medical records-linkage system. METHODS: We designed the REP Data Exploration Portal (REP DEP) to include summary information for people who lived in a 27-county region of southern Minnesota and western Wisconsin on January 1, 2014 (n = 694,506; 61% of the entire population). We obtained diagnostic codes of the International Classification of Diseases, 9th edition, from the medical records-linkage system in 2009 through 2013 (5 years) and grouped them into 717 disease categories. For each condition or combination of 2 conditions (dyad), we calculated prevalence by dividing the number of persons with a specified condition (numerator) by the total number of persons in the population (denominator). We calculated observed-to-expected ratios (OERs) to test whether 2 conditions co-occur more frequently than would co-occur as a result of chance alone. RESULTS: We launched the first version of the REP DEP in May 2017. The REP DEP can be accessed at http://rochesterproject.org/portal/. Users can select 2 conditions of interest, and the REP DEP displays the overall prevalence, age-specific prevalence, and sex-specific prevalence for each condition and dyad. Also displayed are OERs overall and by age and sex and maps of county-specific prevalence of each condition and OER. CONCLUSION: The REP DEP draws upon a medical records-linkage system to provide an innovative, rapid, interactive, free-of-charge method to examine the prevalence and co-occurrence of 717 diseases and conditions in a geographically defined population.

Preeclampsia and ESRD: The Role of Shared Risk Factors.

BACKGROUND: Several registry-based studies, using diagnostic codes, have suggested that preeclampsia is a risk factor for end-stage renal disease (ESRD). However, because the 2 diseases share risk factors, the true nature of their association remains uncertain. Our goals were to conduct a population-based study to determine the magnitude of the association between preeclampsia and ESRD and evaluate the role of shared risk factors. STUDY DESIGN: Population-based nested case-control study. SETTING & PARTICIPANTS: The US Renal Data System was used to identify women with ESRD from a cohort of 34,581 women who gave birth in 1976 to 2010 in Olmsted County, MN. 44 cases of ESRD were identified and each one was matched to 2 controls based on year of birth (±1 year), age at first pregnancy (±2 years), and parity (±1 or ≥4). PREDICTOR: Preeclamptic pregnancy, confirmed by medical record review. OUTCOME: ESRD. MEASUREMENTS: Prepregnancy serum creatinine and urine protein measurements were recorded. Comorbid conditions existing prior to pregnancy were abstracted from medical records and included kidney disease, obesity, diabetes, and hypertension. RESULTS: There was evidence of kidney disease prior to the first pregnancy in 9 of 44 (21%) cases and 1 of 88 (<1%) controls. Per chart review, 8 of 44 (18%) cases versus 4 of 88 (5%) controls had preeclamptic pregnancies (unadjusted OR, 4.0; 95% CI, 1.21-13.28). Results were similar after independent adjustment for race, education, diabetes, and hypertension prior to pregnancy. However, the association was attenuated and no longer significant after adjustment for obesity (OR, 3.25; 95% CI, 0.93-11.37). LIMITATIONS: The limited number of ESRD cases and missing data for prepregnancy kidney function. CONCLUSIONS: Our findings confirm that there is a sizable association between preeclampsia and ESRD; however, obesity is a previously unexplored confounder. Pre-existing kidney disease was common, but not consistently coded or diagnosed.

Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study.

BACKGROUND: Epidemiological studies of drug-induced parkinsonism remain limited. OBJECTIVES: To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population. METHODS: We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine-blocking or dopamine-depleting medications. RESULTS: Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug-induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women. CONCLUSIONS: The incidence of drug-induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Time, Sex, Gender, History, and Dementia.

A growing body of epidemiologic evidence indicates a decline in the incidence or prevalence of dementia in high income countries in the past 25 years. In this commentary, I first suggest that the decline in the incidence or prevalence of dementia is not explained completely by the factors considered so far, and that a broader historical perspective may be needed. Second, I suggest that the overall declining trend may conceal trends in opposite directions for the two major subtypes of dementia, the neurovascular and the neurodegenerative type. Third, I suggest some areas of future research to further elucidate the trends. The future of dementia remains somewhat unclear. Even if the incidence continues to decline, the prevalence may remain the same or increase if survival of persons affected by dementia increases. In addition, even if the prevalence declines, the total number of persons affected by dementia may remain the same or increase if the size of the elderly population expands. Finally, we cannot be sure that the decline in incidence will continue in the coming decades. With cautious optimism, we may conclude that the burden of dementia may be modified over time by human practices, including public health and medicine.

Alzheimer's disease: The next frontier-Special Report 2017.

In the history of medicine, one means to progress is when we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis. This Special Report examines how the development and validation of Alzheimer's disease biomarkers-including those detectable in the blood or cerebral spinal fluid, or through neuroimaging-is a top research priority. This has the potential to markedly change how we diagnose Alzheimer's disease and, as a result, how we count the number of people with this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's disease, we envision a future in which Alzheimer's disease is placed in the same category as other chronic diseases, such as cardiovascular disease or diabetes, which can be readily identified with biomarkers and treated before irrevocable disability occurs.

Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly.

Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-ß load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-ß load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with both vascular and amyloid pathologies, the effect of both pathologies on cognition was additive and not synergistic. For a 79-year-old subject, the predicted annual rate of global z-score decline was -0.02 if on neither pathway, -0.07 if on the vascular pathway, -0.08 if on the amyloid pathway and -0.13 if on both pathways. The main conclusions of this study were: (i) amyloid and vascular pathologies seem to be at least partly independent processes that both affect longitudinal cognitive trajectories adversely and are major drivers of cognitive decline in the elderly; and (ii) cognitive reserve seems to offset the deleterious effect of both pathologies on the cognitive trajectories.