Neuropsychological deficits in sober alcoholics: influences of chronicity and recent alcohol consumption

BACKGROUND: The relationships between severity of neuropsychological (NP) deficits and quantity and duration of alcoholic drinking remain controversial. Eckardt et al. (1998) proposed that NP deficits can be observed only if chronicity of alcohol abuse equals or exceeds 10 years. In this study we tested the hypothesis of Eckardt et al. and reexamined the relationship of NP performance and alcohol consumption. METHODS: One hundred sixty-two alcoholics and 165 controls completed a NP test battery at least 3 weeks after the alcoholics attained sobriety. Chronicity varied from 4 to 9 years for 55 alcoholics and from 10 to 33 years for the remaining 107. RESULTS: Compared to controls, both groups of alcoholics were impaired on the Shipley Vocabulary and Abstraction tests and on two versions of the Digit Symbol test, but there was no difference between the two alcoholic groups on any measure. Regression analyses that controlled for age and education showed that chronicity predicted less than 0.5% of the variance on NP measures. By contrast, a measure of recent alcohol consumption, the Quantity-Frequency Index, contributed significantly (approximately 5% of the variance) to the prediction of alcoholics' NP performance. CONCLUSIONS: These data provide weak support for a dose effect relationship between degree of NP impairment and level of alcoholic drinking in the past 6 months but no evidence for an influence of chronicity.     

Relationships between Neuropsychological Test Performance and Event-Related Potentials in Alcoholic and Nonalcoholic Samples

Are event-related potentials and nonconcurrently measured neuropsychological test performance correlated? Sober male and female middle-aged alcoholics and peer controls were administered an “oddball” event-related potential (ERP) task and several hours later, a battery of neuropsychological (NP) tests. Alcoholics performed significantly poorer than controls on NP tests. Male alcoholics had significantly altered ERP responses (N1, NdA, and P3 amplitudes) but female alcoholics did not differ on any ERP variables from controls. A number of significant correlations between ERP and NP measures were present. The most consistent findings were positive correlations between perceptual-motor (PM) tests and the P3 amplitude at Pz in both male and female alcoholics and in male alcoholics, a negative correlation between PM tests and P3 latency at Pz, findings similar to those seen in Parkinson patients. Significant correlations were most numerous in family history positive alcoholics. The results lead to two conclusions: first, Grant's postulation that sober alcoholics may manifest an intermediate duration organic mental disorder is supported; second, given the lack of ERP differences in the females, ERP measures should not be considered as being causally related to NP performance.     

Chronic Alcoholism in Males: Cognitive Deficit as a Function of Age of Onset, Age, and Duration

Performance on a cognitive rule-learning task was studied in detoxified alcoholics having early/late onset and short-/long-term drinking histories, and in matched nonalcoholic controls. There were pronounced cognitive deficits in early onset and long-term alcoholics. Impairment was severest in the early onset group, even though they were on the average 15 years younger than the late onset group. Early onset alcoholics were relatively more impaired on both the abstract and the verbal Shipley measures. This group also manifested a relative deficit in ability to show positive transfer across problems. Chronicity of alcoholism also interfered with acquisition of an abstract relationship between concrete stimulus attributes. Age negatively influenced ability to perform abstractions, but not commonly tested verbal skills. The findings suggest that an early onset of alcoholism, regardless of duration of problem drinking, is particularly predictive of cognitive impairment.     

Specific Memory Deficits Associated with Prolonged Alcohol Abuse

The relationship between age, education, length and amount of heavy drinking, and performance on five memory tasks was investigated in 54 chronic alcoholics and 18 age-matched controls. Alcoholics with less than 12 yr of heavy drinking differed reliably from long-term (13–22 yr) and extended long-term drinkers (>23 yr) in recognition memory for visual patterns when scores were corrected for age. Compared with controls, both groups of long-term drinkers were deficient on the visual, auditory, and Faces recognition tests. Age and education of alcoholics accounted for part of performance differences; length of alcohol abuse, however, predicted reliably the decline in memory scores on all but the tactual test. The profile of memory performances seemed to decrease linearly with increasing age and length of alcohol abuse.     

Exaggerated exercise blood pressure response in middle-aged men as a predictor of future blood pressure: a 10-year follow-up

Objective: The prognostic value of an exaggerated exercise systolic blood pressure response (EESBPR) remains controversial. This study was designed to assess whether an EESBPR is associated with the predictor of future blood pressure. Methods: From an initial population of 1,534 male-subjects with normal BP or no medication who underwent ergometric exercise, 733 subjects (mean age: 41 years old) at baseline to follow-up BP after an average of 10 years were selected. A 12-min exercise tolerance test with three phases of estimated load from predictive maximum oxygen intake was performed at baseline, and exercise BP was measured. Results: Exercise BP response was classified by three group: Low group (G) (exercise SBP < 180 mmHg), Middle G (exercise BP:180–199 mmHg), High G (exercise BP:200 mmHg ≦). BP after 10 years in Low G was 123 ± 12/79 ± 7 mmHg, in Middle G:127 ± 13/81 ± 8 mmHg, in High G :134 ± 15/84 ± 10 mmHg. Compared with in Low G, BP after 10 years in High G significantly increased (p < 0.05). Multiple regression analysis was carried out to clarify the relationship of exercise SBP at baseline to BP after 10 years. In multivariate-adjusted models, the relationship of SBP at follow-up was stronger to exercise SBP (β = 0.271, P < 0.001) than to resting SBP (β = 0.148, P < 0.001). Maximum oxygen intake (β = ?0.193, P = 0.003) and resting SBP correlated with SBP after 10 years. Conclusions: In middle-aged men, exercise SBP would be a stronger predictor of future SBP, DBP rather than BP at rest. In optimal of classification of BP (SBP < 120 mmHg), exercise BP response was clearly associated with BP after 10 years.     

The relationship of scoring treatment and age in perceptual-integrative performance.

The present study was designed to reexamine the hypothesis that timed perceptual-integrative performance tests are negatively biased measures of the abilities of the elderly. Unlike an earlier study by Doppelt and Wallace (1955) which did not support this hypothesis, the current study consisted of a college-age group in addition to the elderly group, and also included an additional scoring treatment. Each subject was tested with the WAIS Block Design and Object Assembly. Tests were scored in three ways: (1) Standard scoring (WAIS Manual); (2) "regular" scoring (timed, omitting bonus points); (3) "Irregular" scoring (untimed, omitting bonus points). For both tests, Age, Scoring, and the Age by Scoring ineraction were significant. Post hoc analyses for significant effects suggest that the elderly are helped most by additional solution time, whereas younger adults derive greater benefits from the bonus points for quick performance. The results also suggest that subjects must be of sufficiently high ability to effectively use increased or unlimited solution time.     

Patterns of Cognitive Impairment among Alcoholics: Are There Subtypes?

The mild generalized dysfunction hypothesis of alcohol abuse's deleterious effects on cognitive processes has gained support from a number of studies in which detoxified alcoholics have a lower mean performance level than peer controls on a variety of neuropsychological tests. This approach might obscure consistent but different patterns of preserved and impaired cognitive performance among subgroups of alcoholics, suggestive of alternative hypotheses. To test this possibility, neuropsychological test data from two large, independent samples of alcoholics (sample 1, n = 143; sample 2, n = 130) and controls (sample 1, n = 97; sample 2, n = 83) were subjected to separate centroid hierarchical cluster analyses. For both samples, the majority of alcoholics (94% and 94%) exhibited a pattern of impaired verbal and nonverbal performance and deficits in memory and perceptual motor skill, with normal motor skill. The alcoholics who did not fit this pattern showed more severe or wide-ranging impairments. These findings indicate that empirical support for the mild generalized dysfunction hypothesis of alcoholics' cognitive deficits is not an artifact of averaging.     

Correlation between a psychometric test and biochemical indices of hepatic encephalopathy in alcoholics

BACKGROUND/AIMS: In alcohol abusers an alteration of responses to psychometric tests has been reported, even when clinical symptoms of hepatic encephalopathy (HE) are absent. Our research was intended to individualize a simple psychometric test, easy enough to be performed also at the patient's home, able to reveal an impending encephalopathy and, consequently, to facilitate earlier treatment. METHODOLOGY: Twenty-six consecutive male alcoholics were engaged and, after informed consent, the following schedule was applied: administration of a psychometric test, followed by a drawing of blood for the determination of many blood parameters. After 15 days of treatment to detoxicate patients, psychometric tests and blood examinations were repeated. RESULTS: The results confirmed that common blood examinations are not useful to monitor brain damage in chronic alcoholism, that a psychometric test is able to demonstrate a therapeutic improvement and that a positive and significant correlation has been observed between BBCA/AAA ratio and WAIS Score. CONCLUSIONS: These preliminary results suggest that it is possible to suspect dangerous biochemical changes by means of a simple psychometric test.     

Relationship of blood pressure and cardiovascular disease risk factors in normotensive middle-aged men

We conducted this study to investigate whether subjects with high-normal systolic blood pressure (SBP) have an increased risk of cardiovascular disease (CVD) and/or diabetes compared to subjects with low-normal SBP, using metabolic syndrome (MetS) as a risk factor for future CVD/diabetes.The study included 6133 apparently healthy Taiwanese men aged 40-65 years. All subjects were normotensive, and none took medication for any abnormal MetS component. To avoid the effect of age on blood pressure, we stratified patients first by age then by SBP (that is, low, middle, and high SBP). We pooled all the low, middle, and high SBP groups from the different age strata to create 3 larger groups (Group 1, Group 2, and Group 3, respectively). The MetS components in subjects with the lowest SBP (Group 1) were compared with those in the other 2 groups. All of the MetS components, except for high-density lipoprotein cholesterol (HDL-C), were significantly lower in Group 1. Thus, it was not surprising that Group 2 and Group 3 had significantly higher odds ratios for abnormal body mass index, fasting plasma glucose, low-density lipoprotein-cholesterol (LDL-C), and triglycerides than Group 1 (but not for HDL-C). Specifically, Group 3 had a 1.7-fold higher odds ratio (p < 0.001) for having MetS than Group 1. Age, body mass index, fasting plasma glucose, LDL-C, and log triglycerides correlated significantly with SBP. In multivariate linear regression analysis, we found that only body mass index, fasting plasma glucose, and log triglycerides remained significantly related to SBP. Among them, body mass index had the highest β value.In conclusion, the level of SBP was highly correlated with body mass index, fasting plasma glucose, and triglycerides in subjects with normotension. Although there is not a cause-and-effect relationship, the risk of CVD and diabetes was significantly associated with an elevation of SBP, even when the SBP remained within the normal range. Further studies are needed to determine whether normotensive subjects would benefit from medical management.     

Comparative Efficacy of Psychometric Tests in Detection of Subclinical Hepatic Encephalopathy in Nonalcoholic Cirrhotics: Search for a Rational Approach

To compare the efficacy of various psychometric tests in the detection of subclinical hepatic encephalopathy (SHE), cerebral functions were studied in 20 nonalcoholic cirrhotics without overt encephalopathy and in 18 matched healthy controls. Wechsler Adult Intelligence Scale (WAIS) indicated that verbal ability was preserved in all cirrhotics. Of the WAIS performance tests, block design test (BDT) was abnormal in 11 (55%), picture arrangement in 10 (50%), object assembly in eight (40%) and digit symbol in six (30%) patients. Taken together, these tests diagnosed SHE in 14 (70%) patients. Number connection test (NCT) alone, on the other hand, was abnormal in 13 (65%) patients. A combination of NCT and BDT yielded the diagnosis of SHE in 15 (75%) patients. An important measure of the reliability of the diagnosis of SHE was that NCT and BDT were independently abnormal in 10 of these patients. Both NCT and BDT were found easy and quick to administer. In conclusion, our results argue in favor of using a combination of NCT and BDT for a rapid and accurate diagnosis of SHE in patients with cirrhosis of the liver.     

Age and Alcoholism: Independent Memory Decrements

Similarities and differences in performances on 18 verbal and nonverbal memory tasks were studied in young and old alcoholics and in young and old controls as test of hypotheses postulating that cognitive decrements from alcoholism either mimic "premature aging," are "age sensitive," or are "independent" from those of normal aging. Young and old alcoholics were matched in length and rate of heavy drinking and were also equated with their controls in age, education, and vocabulary. The multivariate memory and decision data, when converted to independent factor scores, separated alcoholic from control groups on a factor reflecting memory for auditorily presented information. This was independent from factor scores affected mainly by age, such as memory for visuospatial items or decision bias. Age and alcoholism produced overlapping but distinctly different profiles of memory impairments. Decrements in young alcoholics did not resemble those of aging nor did old alcoholics surpass old controls in any but one factor, so that neither the premature aging nor the age sensitivity hypothesis were invariably supported.     

Serum mitochondrial aspartate aminotransferase as a marker of chronic alcoholism: diagnostic value and interpretation in a liver unit

Serum mitochondrial aspartate aminotransferase activity was measured using an immunochemical method in 251 subjects, of whom 140 were chronic alcoholics. The alcoholic patients included 37 with normal liver routine tests (Group I), 61 with noncirrhotic alcoholic liver disease (Group II) and 42 with cirrhosis (Group III), of whom 21 had been abstainers for at least 2 months. All of the remaining 111 subjects were nonalcoholic: 61 had various types of liver disease (Group IV) and 50 were healthy controls. A second assay of serum mitochondrial aspartate aminotransferase activity was performed in 76 alcoholics after a period of abstinence of about 7 days. In addition, serial mitochondrial aspartate aminotransferase determinations were performed in four nonalcoholic volunteers prior to, during and following an alcohol bout. Mean mitochondrial aspartate aminotransferase and mitochondrial aspartate aminotransferase/total aspartate aminotransferase ratio were significantly increased in the alcoholics whatever their liver status, with a sensitivity of the ratio of 81, 85 and 66% for Group I, Group II and the 21 drinkers of Group III, respectively. Only 1 of the 21 cirrhotic abstainers had an increased ratio. Among the 61 nonalcoholic patients with liver disease, 11 had an increased mitochondrial aspartate aminotransferase/total aspartate aminotransferase ratio, specificity of which was 82%. After drinking had been stopped for about 1 week, mitochondrial aspartate aminotransferase decreased by more than 50% and therefore appears as a reliable tool to assess abstinence. In the four cases of alcohol bouts, no significant modifications in mitochondrial aspartate aminotransferase serum values were observed, thus suggesting that mitochondrial aspartate aminotransferase is indeed a marker of chronic, but not of acute, alcohol intake.     

不同血糖负荷早餐对2型糖尿病患者餐后血糖及C肽的影响

目的探讨试食不同血糖负荷（GL）早餐对2型糖尿病患者餐后血糖和C肽的影响,为GL概念在糖尿病营养宣教和饮食干预中的应用提供理论依据。方法将74例2型糖尿病受试者随机分为A、B两组,每组37例。给予A组混合餐a（GL33．6）;给予B组混合餐b（GIA3．0）。从A组中随机抽取14例受试者构成C组,使其分别再于不同的两日分别试食混合餐C（GL34．6）和混合餐d（GL54．2）。观察受试者空腹和餐后2h血糖、C肽的变化情况,并运用统计学软件SPSSl9．0数据包对数据进行分析处理。结果A组的餐后2h血糖低下B组,差异具有统计学意义;比较试食3种不同混合餐后C组指标后发现试食d餐后的2hPG和2hC—P低于试食a餐和c餐,差异具有统计学意义;试食a餐与C餐后此两者无统计学差异。结论低GL饮食对糖尿病患者餐后血糖的控制具有一定作用,应考虑将其进一步推广于糖尿病的营养宣教和饮食干预中。     

Hepatic resection for hepatocellular carcinoma in severely cirrhotic livers

BACKGROUND/AIMS: Liver resection for hepatocellular carcinoma is typically avoided in patients with severe cirrhosis, as this may predispose patients to pronounced surgical risks and worse long-term outcomes. This study examined our results of hepatectomy for hepatocellular carcinoma in patients with different degrees of impaired liver function. METHODOLOGY: A retrospective comparison of background characteristics and operative results in patients with resected hepatocellular carcinoma was performed, with patients classified as having either severely impaired liver function (High Group, preoperative indocyanine green 15-minute retention rate > or = 30%; n = 22) or normal liver function (Low Group, indocyanine green 15-minute retention rate < or = 10%; n = 37). RESULTS: The preoperative liver function of those in the High Group was significantly worse than those in the Low Group. Despite similar tumor diameters between groups, the amount of liver resected in the High Group was significantly smaller than in the Low Group, primarily because of more limited resections with narrow margins in the former. However, patients in the High Group had similar recurrence and survival rates when compared to those in the Low Group whose resections included wide surgical margins. In analyzing those that did or did not undergo transcatheter arterial chemoembolization prior to resection, a better disease-free and actuarial survival rate was observed in the High Group with preoperative transcatheter arterial chemoembolization compared to those without transcatheter arterial chemoembolization or those in the Low Group with transcatheter arterial chemoembolization. CONCLUSIONS: For patients with limited liver function reserve, such as those in the High Group, resection of hepatocellular carcinoma with preservation of liver parenchyma may take priority over a wide resection margin. In addition, we suggest the use of preoperative transcatheter arterial chemoembolization in selected patients with severe cirrhosis undergoing resection of hepatocellular carcinoma.     

Echocardiographic abnormalities in chronic asymptomatic alcoholics

Alcohol abuse is a frequent contributor to elevated blood pressure, but the literature is ambiguous about the role of hypertension in producing left ventricular dysfunction. Fifty asymptomatic male alcoholics admitted for detoxification were studied using echocardiograms and systolic time intervals. Alcoholics were separated into Group I (28 with hypertension) and Group II (22 without hypertension). Forty-four patients had analyzable echocardiograms and were compared to 29 nonalcoholics. Group III consisted of 14 nonalcoholics with hypertension. Group IV consisted of 15 normotensive nonalcoholics (controls). The ejection fraction and shortening fraction were reduced in Group I (p less than 0.05). Hypertensive alcoholics had increased left ventricular mass indices but less than hypertensive nonalcoholics. Left ventricular wall stress was compared to mass as an index of ventricular compensation. The wall stress to mass index for hypertensive alcoholics was 1.65 as compared to 1.43 for the controls. Alcoholics without hypertension had a wall stress to mass ratio of 1.54. Hypertensive patients had a reduced wall stress to mass ratio of 1.38 when compared to controls. These data suggest an inappropriate compensatory response to afterload. Alcohol and hypertension combined may be more harmful to left ventricular function than either disease alone.     

Premature Aging in Male Alcoholics: “Accelerated Aging” or “Increased Vulnerability”?

This study involved an evaluation of two versions of the "premature aging" theory of chronic alcoholism: the accelerated aging and increased vumerabHty versions. The major dependent measures used were the tests included in Reitan's brain age quotient (BAO), a series of neuropsychological tests known to be sensitive to the effects of alcoholism and aging. Subjects were 40 chronic alcoholic inpatients and 40 matched controls, divided into age groups by; decade, ranging from the 30s to the 60s. It was proposed that an j interaction between age and presence or absence of alcoholism, with BAO test differences between alcoholics and controls widening as age increases, would support the increased vulnerability version, while the absence of such aw interaction would support the accel-] erated aging version. The results dearty favored the accelerated aging version, with merited BAO test differences between alcoholics, and controls appearing even in the 30-year-old groups. It was concluded that chronic ateohoftcs tend to perform at levels found for nonalconoiics 10 years their senior, but the discrepancy between, alcoholics and nonalcohoics does not increase with age.     

Relationship between Serum Cortisol, Liver Function, and Depression in Detoxified Alcoholics

High levels of serum cortisol or abnormal dexamethasone suppression tests may be helpful in diagnosing major depressive disorder. However, a controversy exists as to whether abnormal liver function associated with alcohol abuse may negate the diagnostic value of the dexamethasone suppression test in alcoholics. We investigated the value of the dexamethasone suppression test in alcoholics by analyzing the liver function, cortisol levels, and psychiatric status of inpatients from an alcohol detoxification treatment center. The subjects met the DSM III criteria for alcohol dependence but took no chronic medication and had negative screening for substance abuse. They had routine blood screening to evaluate liver function, the afternoon cortisol test and dexamethasone suppression test to study glucocorticoid activity, and a structured evaluation to determine psychiatric diagnoses. The blood chemistry findings demonstrated a lack of significant liver synthetic dysfunction in this group, although 43% of the subjects had some elevation of their liver enzymes. We did not find differences in the liver function between patients with normal and abnormal cortisol levels. However, subjects with endogenous depression did have significantly elevated afternoon cortisol levels, and they tended to have more normal liver tests. These results indicate that modest liver dysfunction does not contaminate the validity of the plasma cortisol tests or the dexamethasone suppression test as diagnostic tools for assessing depression in this group of detoxified alcoholics. In addition, they demonstrate an association between depression and plasma cortisol levels and suggest a correlation between depression and better liver function in alcoholics who seek detoxification.     

Further Evidence for a Continuum-of-Impairment Encompassing Male Alcoholic Korsakoff Patients and Chronic Alcoholic Men

A battery of challenging tests was used to assess learning ability and short-term memory in groups of detoxified chronic alcoholics with and without complaints of memory impairment, alcoholic Korsakoff patients, and nonalcoholic controls. While alcoholics without memory complaints did not differ from controls on standardized clinical memory tests, their performance was significantly impaired on our more demanding experimental tests. In contrast, the performance of alcoholics reporting memory complaints was impaired, relative to the other alcoholics, on both clinical and experimental memory tests, overlapping that of the alcoholic Korsakoff patients. These results are consonant with Ryback's continuum-of-impairment hvnothesis.     

Perceptual learning in detoxified alcoholic men: contributions from explicit memory, executive function, and age

BACKGROUND: Visuospatial and visuoperceptual deficits have consistently been observed in detoxified alcoholics; however, the severity of impairment varies with test and task type. Identifying the component processes and factors that underlie a particular deficit may reveal why some visuospatial and visuoperceptual tasks are more compromised than others and may lead to the specification of neural systems that are particularly vulnerable in alcoholism. METHODS: We examined visuoperception and perceptual learning with a picture fragment identification task in 51 recently detoxified nonamnesic alcoholic men (aged 29-66 years) compared with 63 normal control men (aged 21-70 years). Executive function and explicit declarative memory were also assessed. RESULTS: Despite deficits in the primary components of visuoperception and explicit memory for visuospatial stimuli, the alcoholics showed normal perceptual learning. Although the alcoholics and controls performed at comparable levels on the perceptual learning task, multiple regression analyses indicated that the factors accounting for perceptual learning variance differed between and within groups. Visuoperceptual abilities consistently predicted perceptual learning in the control subjects but not the alcoholic subjects. Explicit memory contributed to perceptual learning performance in both the alcoholic and control groups. Frontal executive ability consistently predicted perceptual learning in the alcoholic subjects, but it had predictive ability only in the control subjects as time elapsed. Age was significantly correlated with perceptual learning performance in both groups. Lifetime alcohol consumption, but not alcoholism duration, was an independent predictor of 1-hr perceptual learning. CONCLUSIONS: These correlational analyses suggest that controls invoke basic visuospatial processes to perform a perceptual learning task, whereas alcoholics invoke higher-order cognitive processes (i.e., frontal executive systems) to perform the same task at normal levels. Use of more demanding cognitive systems by the alcoholics may be less efficient and more costly to processing capacity than those invoked by controls.     

Low ambulatory blood pressure is associated with lower cognitive function in healthy elderly men

INTRODUCTION: Low blood pressure (BP) has been found to be associated with cerebrovascular damage in the elderly. Studies of the relation of ambulatory BP to cognitive function in elderly persons aged 80 years or above is lacking, however. METHODS: Ninety-seven 81-year-old men from the population study 'Men born in 1914' underwent ambulatory BP monitoring and were given a cognitive test battery, 79 subjects completing all six tests. Low ambulatory systolic blood pressure (SBP) was defined as <130 mmHg and low ambulatory diastolic blood pressure (DBP) as <80 mmHg (corresponding in terms of office BP to approximately <140 and <90 mmHg, respectively). Odds ratios (OR) for lower cognitive function were calculated using a forward stepwise logistic regression model, controlling for confounding factors. RESULTS: Subjects with ambulatory SBP <130 mmHg had higher OR values for daytime (OR 2.6; P=0.037), nighttime (OR 3.6; P=0.032) and 24h (OR 2.6; P=0.038) BP measurements. A lower cognitive function was associated with lower nighttime SBP and DBP levels and lower 24-h mean SBP compared to subjects with higher cognitive function. OR values connected to low nocturnal SBP, had a tendency to be particularly high among subjects on anti-hypertensive drugs (OR 9.1; P=0.067, n.s.). CONCLUSION: Ambulatory SBP levels <130 mmHg and lower nighttime SBP and DBP were associated with lower cognitive function in healthy elderly men. Further investigation is needed to ascertain the effects of the presently recommended treatment goal of <140 mmHg for office SBP also on elderly over 80 years of age.