Search PubMed⌕ Search

Biomedical subjects

D A Bennett

Publications and source records attributed to D A Bennett.

At least 19 recordsLinked to original sources

Education modifies the relation of AD pathology to level of cognitive function in older persons.

OBJECTIVE: To test the hypothesis that years of formal education modifies the relation of AD pathology to level of cognitive function. METHODS: A total of 130 older Catholic clergy participating in the Religious Orders Study underwent annual cognitive function testing and brain autopsy at the time of death. Individual cognitive function tests were z-scored and averaged to yield a global measure of cognitive function and summary measures of five different cognitive abilities. Neuritic and diffuse plaques and neurofibrillary tangles were counted in separate 1 mm(2) areas of maximal density. Counts were converted to standard scores by dividing by their SD, and combined to yield a global AD pathology score and summary scores of each postmortem index. Linear regression was used to examine the relation of education and AD pathology scores to level of cognitive function proximate to death, controlling for age and sex. Subsequent analyses tested the interaction between education and each AD pathology score to determine whether education modified the relation of AD pathology to level of cognitive function. Additional analyses examined these associations on five specific cognitive abilities. RESULTS: Both years of formal education (regression coefficient = 0.073, p = 0.0001) and the global AD pathology score (regression coefficient = -0.689, p < 0.0001) were related to level of cognitive function. When an interaction term between education and AD pathology was added to the model, the association between a unit of AD pathology and level of cognitive function was 0.088 (p = 0.0078) standard unit less for each year of education than the level predicted from the model without the interaction term. Whereas neuritic plaques, diffuse plaques, and neurofibrillary tangles were all strongly related to cognitive function, education only modified the relation of neuritic plaques (p = 0.002) and diffuse plaques (p = 0.03) to cognition, but not neurofibrillary tangles. In analyses examining five different cognitive abilities, the interaction between education and the neuritic plaque score was strongest for perceptual speed and weakest for episodic memory. CONCLUSIONS: These data provide strong evidence that the relation between senile plaques and level of cognitive function differs by years of formal education.

Aged↗

Gender, cognitive decline, and risk of AD in older persons.

BACKGROUND: Cross-sectional studies suggest gender differences in cognitive function and risk of AD in older persons. However, longitudinal studies comparing change in cognitive function and risk of AD in men and women have had mixed results. The authors investigated gender differences in rate of decline for different cognitive systems and for risk of developing AD. METHODS: Participants were from the Religious Orders Study, a longitudinal, clinical-pathologic study of aging and AD in older Catholic nuns, priests, and brothers. Longitudinal data were available from 577 older women and 271 older men, who completed an average of 5.8 annual evaluations with more than 95% follow-up participation in survivors. The evaluations included 21 neuropsychological tests, from which summary measures of global cognitive function and 5 functional domains were formed, and clinical classification of AD. RESULTS: Random effects models were used to analyze change in cognitive function, and proportional hazards models were used to assess risk of incident AD. On average, men and women declined in all abilities during the 8-year period but did not differ in annual rates of change in analyses that controlled for age, education, and initial level of cognitive function. Risk of incident AD did not differ between men and women. Furthermore, results were unchanged after controlling for possession of the apolipoprotein-epsilon4 allele. Duration of estrogen use was related to rate of global cognitive decline and visuospatial abilities in women but did not influence comparisons between men and women in cognitive decline. CONCLUSIONS: The results suggest that patterns of cognitive decline and incidence of AD are similar in older men and women.

Aged↗

Terminal decline in cognitive function.

BACKGROUND: Impending death is thought to be associated with age-related cognitive decline, but this association has not been well studied. METHODS: Participants were 763 older Roman Catholic nuns, priests, and brothers without dementia at baseline. They completed an average of 5.6 annual evaluations (range 2 to 9), with >95% follow-up participation in survivors. Each evaluation included administration of 19 cognitive function tests from which previously established measures of global cognition (mean = 0.108, SD = 0.502) and specific cognitive functions were derived. In a series of change point random effects models, the average point before death when rate of cognitive decline changed was identified, and rates of cognitive decline before and after the optimal change point were estimated, controlling for the effects of age, sex, and education. RESULTS: There were 122 deaths during the observation period. Those who died had lower global cognitive function at baseline than survivors (by 0.103 unit; p = 0.03), and beginning about 43 months before death, their annual rate of global cognitive decline sharply accelerated from an annual loss of 0.026 to 0.173 unit, a more than sixfold increase. Results were comparable in analyses that controlled for baseline health and disability. Terminal cognitive decline was evident in nearly all of those who died, but at highly variable rates. Remarkably little cognitive decline was evident in survivors. Decline in episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability also greatly increased about 3 to 6 years prior to death. CONCLUSION: On average, cognitive decline sharply accelerates in the last years of life.

Age Factors↗

Relation of cerebral infarctions to dementia and cognitive function in older persons.

BACKGROUND: Cerebral infarctions are common in older persons but their relationship with dementia and cognitive function remains controversial. METHODS: Participants were 164 older Catholic nuns, priests, and brothers who underwent annual clinical evaluation and brain autopsy at death. The authors quantified number and volume of old cerebral infarctions on postmortem examination and determined the association with dementia and cognitive function proximate to death. Analyses controlled for age, sex, and education. RESULTS: A total of 58 (35.4%) subjects had cerebral infarctions: 29 had one infarction and 29 had multiple infarctions. In logistic regression analyses, infarctions increased the odds of dementia twofold (OR 2.12; 95% CI 1.06 to 4.25). The odds of dementia increased by 2.67-fold for multiple infarctions (95% CI 1.08 to 6.61), whereas the odds of dementia with single infarctions increased by 69% (95% CI 0.70 to 4.09). In linear regression analyses, there was a trend for multiple infarctions to be associated with lower global cognitive scores (-0.44 standard units, p = 0.057). Multiple infarctions were related to perceptual speed, visuospatial skills, and working memory, but not to episodic or semantic memory. The authors found similar results with infarction volume. In secondary analyses, only infarctions that were clinically evident during life were associated with dementia and cognitive function. CONCLUSION: Cerebral infarctions are associated with a twofold increase in odds of dementia. Odds are higher in persons with multiple, large, or clinically evident infarctions. In addition, cerebral infarctions do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory.

Aged↗

Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease.

OBJECTIVE: To test the hypothesis that the APOE epsilon4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease. METHODS: Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more epsilon4 alleles. RESULTS: In logistic regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the epsilon allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the epsilon4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). CONCLUSIONS: The APOE epsilon4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.

Age Factors↗

Blood pressure and cardiovascular disease in the Asia Pacific region.

OBJECTIVES: To estimate age-, sex- and region-specific associations of blood pressure with cardiovascular diseases. DESIGN: Relative risk estimates and 95% confidence intervals were calculated from Cox models, stratified by sex and cohort, and adjusted for age at risk on individual participant data from 37 cohort studies. Repeat measurements of blood pressure were used to adjust for regression dilution bias. SETTING: Studies included in the Asia Pacific Cohort Studies Collaboration from Australia, mainland China, Hong Kong, Japan, New Zealand, Singapore, South Korea, and Taiwan. PARTICIPANTS: A total of 425 325 study participants. MAIN OUTCOMES MEASURES: Stroke, ischaemic heart disease, total cardiovascular death. RESULTS: During over 3 million person-years of follow-up, 5178 strokes, 3047 ischaemic heart disease events and 6899 cardiovascular deaths were observed. Continuous log-linear associations were seen between systolic blood pressure and the risks of all three endpoints down to at least 115 mmHg. In the age groups < 60, 60-69, and > or = 70 years, a 10 mmHg lower usual systolic blood pressure was associated with 54% (95% CI 53-56%), 36% (34-38%) and 25% (22-28%) lower stroke risk, and 46% (43-49%), 24% (21-28%) and 16% (13-20%) lower ischaemic heart disease risk, respectively. All associations were similar in men and women. Blood pressure was at least as strongly associated with cardiovascular events in Asian populations compared to Australasian populations. CONCLUSIONS: About half of the world's cardiovascular burden is predicted to occur in the Asia Pacific region. Blood pressure is an important determinant of this burden, with considerable potential benefit of blood pressure lowering down to levels of at least 115 mmHg systolic blood pressure.

Aged↗

Cognitive activity and incident AD in a population-based sample of older persons.

BACKGROUND: Participation in cognitively stimulating activities is hypothesized to be associated with risk of AD, but knowledge about this association is limited. METHODS: A biracial community in Chicago was censused, persons aged 65 years and older were asked to participate in an interview, and 6,158 of 7,826 (79%) eligible persons did so. As part of the interview, persons rated current frequency of participation in seven cognitive activities (e.g., reading a newspaper) and nine physical activities (e.g., walking for exercise) from which composite measures of cognitive and physical activity frequency were derived. Four years later, 1,249 of those judged free of AD were sampled for a detailed clinical evaluation of incident disease and 842 (74% of those eligible) participated. RESULTS: The composite measure of cognitive activity ranged from 1.28 to 4.71 (mean 3.30; SD 0.59), with higher scores indicating more frequent activity. A total of 139 persons met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD on clinical evaluation. In a logistic regression model adjusted for age, education, sex, race, and possession of the APOE epsilon4 allele, a one-point increase in cognitive activity score was associated with a 64% reduction in risk of incident AD (OR 0.36; 95% CI 0.20 to 0.65). By contrast, weekly hours of physical activity (mean 3.5; SD 5.1) was not related to disease risk (OR 1.04; 95% CI 0.98 to 1.10). Education was associated with risk of AD and a similar trend was present for occupation, but these effects were substantially reduced when cognitive activity was added to the model. CONCLUSION: Frequency of participation in cognitively stimulating activities appears to be associated with risk of AD and may partially explain the association of educational and occupational attainment with disease risk.

Aged↗

Depressive symptoms, cognitive decline, and risk of AD in older persons.

BACKGROUND: Cross-sectional and retrospective case-control studies suggest an association of depression symptoms with cognitive impairment and AD, but there have been few prospective studies and their results have been inconsistent. METHODS: Participants are Catholic clergy members who were aged > or =65 years and who did not have clinical evidence of AD. During a 7-year period, they underwent annual clinical evaluations that included clinical classification of AD and detailed cognitive function testing from which global and specific measures of cognition were derived. Number of depressive symptoms was assessed at baseline with a modified, 10-item Center for Epidemiologic Studies Depression Scale (CES-D). The association of CES-D score with incident AD, using proportional hazards models, and cognitive decline, using random effects models, was examined. RESULTS: At baseline, participants reported an average of about one depressive symptom on the CES-D scale (range, 0 to 8). During the 7 years of follow-up, 108 persons developed AD. In analyses that controlled for selected demographic and clinical variables including baseline level of cognitive function, CES-D score was associated with both risk of AD and rate of cognitive decline. For each depressive symptom, risk of developing AD increased by an average of 19%, and annual decline on a global cognitive measure increased by an average of 24%. CONCLUSIONS: The results raise the possibility that depressive symptoms in older persons may be associated with risk of developing AD.

Aged↗

Natural history of mild cognitive impairment in older persons.

BACKGROUND: Cognitive abilities of older persons range from normal, to mild cognitive impairment, to dementia. Few large longitudinal studies have compared the natural history of mild cognitive impairment with similar persons without cognitive impairment. METHODS: Participants were older Catholic clergy without dementia, 211 with mild cognitive impairment and 587 without cognitive impairment, who underwent annual clinical evaluation for AD and an assessment of different cognitive abilities. Cognitive performance tests were summarized to yield a composite measure of global cognitive function and separate summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The authors compared the risk of death, risk of incident AD, and rates of change in global cognition and different cognitive domains among persons with mild cognitive impairment to those without cognitive impairment. All models controlled for age, sex, and education. RESULTS: On average, persons with mild cognitive impairment had significantly lower scores at baseline in all cognitive domains. Over an average of 4.5 years of follow-up, 30% of persons with mild cognitive impairment died, a rate 1.7 times higher than those without cognitive impairment (95% CI, 1.2 to 2.5). In addition, 64 (34%) persons with mild cognitive impairment developed AD, a rate 3.1 times higher than those without cognitive impairment (95% CI, 2.1 to 4.5). Finally, persons with mild cognitive impairment declined significantly faster on measures of episodic memory, semantic memory, and perceptual speed, but not on measures of working memory or visuospatial ability, as compared with persons without cognitive impairment. CONCLUSIONS: Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.

Aged↗

Progression of gait disorder and rigidity and risk of death in older persons.

BACKGROUND: Bradykinesia, gait disturbance, rigidity, and tremor are common motor signs in old age. All of these signs are associated with increased morbidity and mortality, but the extent to which they are progressive is unknown. METHODS: Study participants were 787 older Catholic clergy members without clinically diagnosed PD, related conditions, or dementia at baseline. They were evaluated annually for up to 7 years, with >95% follow-up participation by survivors. Evaluations included administration of a modified version of the motor portion of the Unified PD Rating Scale (UPDRS), from which previously established measures of the global UPDRS and four specific motor signs were derived. Scores represent the percent of the total possible UPDRS score obtained. RESULTS: At baseline, the global UPDRS score ranged from 0 to 36.3 (mean +/- SD, 7.3 +/- 6.4). It increased by an average of 0.69 unit per year during follow-up, with more rapid progression in older persons, but there was wide variability with no progression in 21% of subjects and annual increases of up to 8.23 units in the remaining 79%. Of 129 persons who died, 106 had follow-up UPDRS data. In a proportional hazards model, risk of death was associated with both the level of the global UPDRS score at baseline and the annual rate of progression (both p < 0.001). Overall, risk of death in subjects who had some worsening of the global UPDRS score was 2.93 times the rate among those without progression (95% CI, 1.32-6.50). Gait disorder/postural reflex impairment and rigidity worsened, but bradykinesia and tremor did not. Risk of death was associated with worsening of gait/posture but not with the other signs. CONCLUSION: Gait disorder and rigidity, as assessed with the modified UPDRS, are usually progressive in old age. Both the severity of the gait disorder and its rate of progression are strongly associated with risk of death.

Aged↗

Subarachnoid haemorrhage occurrence exhibits a temporal pattern - evidence from meta-analysis.

The aim of the present meta-analysis was to determine a temporal pattern of occurrence of subarachnoid haemorrhage (SAH). A MEDLINE 1966-2001 and EMBASE (1980-2001) literature search and hand search of relevant references were performed for population-based incidence studies that reported the time of SAH occurrence. Data from all identified relevant studies were combined into a pooled rate ratio (RR), with corresponding 95% confidence intervals (CI) using the Mantel-Haenszel method. Overall, eight population-based studies were included in the analysis. A total of 2533 first-ever cases of SAH were reported in the studies identified. Risk of SAH occurrence was the highest in the period between 6 am and 12 am (RR = 3.19; 95% CI 3.03-3.36; early morning as a reference variable) and between 12 p.m. and 6 p.m. (RR = 2.63; 95% CI 2.47-2.80), in winter and spring (RR = 1.10; 95% CI: 1.02-1.17; and RR = 1.07; 95% CI: 1.01-1.13, respectively; summer as a reference variable) and on Sunday (RR = 1.22; 95% CI 1.09-1.37; Monday as a reference variable). The evidence suggests that occurrence of SAH exhibits a seasonal (winter and spring) peak, diurnal (late morning peak) and daily (Sunday peak) pattern. It is suggested that the occurrence of some major acute vascular events (total ischaemic strokes, intracerebral haemorrhage and myocardial infarction) may be influenced by common triggering factors.

Circadian Rhythm↗

The apolipoprotein E epsilon 2 allele and decline in episodic memory.

OBJECTIVES: The apolipoprotein E (apoE) epsilon 4 allele is related to decline in multiple cognitive domains, especially episodic memory, but the effect of the epsilon 2 allele on change in different forms of cognitive function has been difficult to establish. METHODS: Participants are from the Religious Orders Study. At baseline, they were at least 65 years old and free of clinical evidence of dementia. For up to eight years, they underwent annual clinical evaluations that included detailed cognitive function assessment from which previously established summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability were derived. Growth curve models were used to assess change in each measure and its relation to apoE genotype, controlling for age, sex, education, and baseline level of cognition. Follow up data were available in 669 persons (98% of those eligible). We treated those with the epsilon 3/3 genotype as the reference group (n=425), which was contrasted with epsilon 2 ( epsilon 2/2, epsilon 2/3; n=86), and epsilon 4 ( epsilon 3/4, epsilon 4/4; n=158) subgroups. RESULTS: Rate of episodic memory change in the three subgroups significantly differed, with an average annual increase of 0.016 units in the epsilon 2 subgroup and annual decreases of 0.022 units in those with epsilon 3/3 and of 0.073 units in the epsilon 4 subgroup. The epsilon 2 subgroup did not differ from those with epsilon 3/3 in rate of decline in other cognitive systems. The epsilon 4 subgroup declined more rapidly than those with epsilon 3/3 in semantic memory and perceptual speed but not in working memory or visuospatial ability. CONCLUSION: Possession of one or more apoE epsilon 2 alleles is associated with reduced decline in episodic memory in older persons.

Aged↗

Down-regulation of trkA mRNA within nucleus basalis neurons in individuals with mild cognitive impairment and Alzheimer's disease.

Recent studies indicate that trkA expression is reduced in end-stage Alzheimer's disease (AD). However, understanding the neuropathologic correlates of early cognitive decline, as well as the changes that underlie the transition from nondemented mild cognitive impairment (MCI) to AD, are more critical neurobiological challenges. In these regards, the present study examined the expression of trkA mRNA in individuals diagnosed with MCI and AD from a cohort of people enrolled in a Religious Orders Study. Individuals with MCI and AD displayed significant reductions in trkA mRNA relative to aged-matched controls, indicating that alterations in trkA gene expression occur early in the disease process. The magnitude of change was similar in MCI and AD cases, suggesting that further loss of trkA mRNA is not necessarily associated with the transition of individuals from nondemented MCI to AD. The loss of trkA mRNA was not associated with education, apolipoprotein E allele status, gender, Braak score, global cognitive score or Mini-Mental Status Examination. In contrast, the loss of trkA mRNA in MCI and AD was significantly correlated with function on a variety of episodic memory tests.

Aged↗

Mechanism of sulfide oxidations by peroxymonocarbonate.

A detailed mechanism for the oxidation of aryl sulfides by peroxymonocarbonate ion in cosolvent/water media is described. Kinetic studies were performed to characterize the transition state, including a Hammett correlation and variation of solvent composition. The results are consistent with a charge-separated transition state relative to the reactants, with an increase of positive charge on the sulfur following nucleophilic attack of the sulfide at the electrophilic oxygen of peroxymonocarbonate. In addition, an average solvent isotope effect of 1.5 +/- 0.2 for most aryl sulfide oxidations is consistent with proton transfer in the transition state of the rate-determining step. Activation parameters for oxidation of ethyl phenyl sulfide in tert-butyl alcohol/water are reported. From the pH dependence of oxidation rates and (13)C NMR equilibrium experiments, the estimated pK(a) of peroxymonocarbonate was found to be approximately 10.6.

Journal Article↗

Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study.

BACKGROUND: It is uncertain whether high blood pressure increases the risk of developing Alzheimer disease (AD). OBJECTIVE: To examine the association between incident AD and blood pressure measured up to 13 years before diagnosis. DESIGN: Longitudinal cohort study conducted from 1982 to 1988, with blood pressure measured every 3 years in home interviews, and in 1973 for a portion (60%) of the sample. SETTING: Community of East Boston, Mass. PARTICIPANTS: Six hundred thirty-four subjects 65 years or older and without AD were selected as a stratified random sample of participants of the East Boston Established Populations for Epidemiologic Studies of the Elderly. MAIN OUTCOME MEASURE: Alzheimer disease was diagnosed by a neurologist using a structured clinical evaluation. RESULTS: High blood pressure was not associated with an increased risk of AD in logistic regression models adjusted for age, sex, and level of education. There was no association with systolic pressure measured 13 years before diagnosis (odds ratio = 1.03/10 mm Hg; 95% confidence interval, 0.80-1.32) and an inverse association with systolic pressure measured 4 years before diagnosis (odds ratio = 0.82/10 mm Hg; 95% confidence interval, 0.72-0.95). Associations for diastolic pressure were in the same direction as those for systolic pressure except with wider confidence intervals. The odds ratios were not materially different with further adjustment for cardiovascular risk factors and diseases. CONCLUSION: In this large community study, high blood pressure was not associated with an increased risk of AD.

Aged↗

Evaluating nonpoint pollution policy using a tightly coupled spatial decision support system.

Policy makers often must rely on the cumulative impact of independent actions taken by local landowners to achieve environmental goals. The connection between policy, regulation, and local action, however, is often not well understood and, thus, the impact of proposed policies may be difficult to predict. In this study we evaluate the effectiveness of alternative policy scenarios for agricultural set aside programs (e.g., the conservation reserve program administered by the United States Department of Agriculture) in reducing nonpoint pollution. Two alternative policy scenarios are developed and analyzed; one based on the erodibility index (detachment), the other sediment yield (transport). An estimate of the cumulative impact of associated land use change on nonpoint pollution is made using the AGNPS distributed parameter watershed model. This work is completed within the Cypress Creek watershed in southern Illinois. An analysis of the resulting data suggests that the most efficacious regulatory strategy for achieving nonpoint water pollution goals depends, in part, on place-specific land use patterns. This conclusion provides a solid argument for place-based regulatory strategies.

Agriculture↗

How can I deal with missing data in my study?

Missing data in medical research is a common problem that has long been recognised by statisticians and medical researchers alike. In general, if the effect of missing data is not taken into account the results of the statistical analyses will be biased and the amount of variability in the data will not be correctly estimated. There are three main types of missing data pattern: Missing Completely At Random (MCAR), Missing At Random (MAR) and Not Missing At Random (NMAR). The type of missing data that a researcher has in their dataset determines the appropriate method to use in handling the missing data before a formal statistical analysis begins. The aim of this practice note is to describe these patterns of missing data and how they can occur, as well describing the methods of handling them. Simple and more complex methods are described, including the advantages and disadvantages of each method as well as their availability in routine software. It is good practice to perform a sensitivity analysis employing different missing data techniques in order to assess the robustness of the conclusions drawn from each approach.

Bias↗

Impaired production priming and intact identification priming in Alzheimer's disease.

This study examined the distinction between identification and production processes in repetition priming for 16 patients with Alzheimer's disease (AD) and 16 healthy old control participants (NC). Words were read in three study phases. In three test phases, participants (1) reread studied words, along with unstudied words, in a word-naming task (identification priming); (2) completed 3-letter stems of studied and unstudied words into words in a word-stem completion task (production priming); and (3) answered yes or no to having read studied and unstudied words in a recognition task (explicit memory). Explicit memory and word-stem completion priming were impaired in the AD group compared to the NC group. After correcting for baseline slowing, word-naming priming magnitude did not differ between the groups. The results suggest that the distinction between production and identification processes has promise for explaining the pattern of preservation and failure of repetition priming in AD.

Aged↗