Association of hearing impairment with brain volume changes in older adults.

Hearing impairment in older adults is independently associated in longitudinal studies with accelerated cognitive decline and incident dementia, and in cross-sectional studies, with reduced volumes in the auditory cortex. Whether peripheral hearing impairment is associated with accelerated rates of brain atrophy is unclear. We analyzed brain volume measurements from magnetic resonance brain scans of individuals with normal hearing versus hearing impairment (speech-frequency pure tone average>25 dB) followed in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging for a mean of 6.4 years after the baseline scan (n=126, age 56-86 years). Brain volume measurements were performed with semi-automated region-of-interest (ROI) algorithms, and brain volume trajectories were analyzed with mixed-effect regression models adjusted for demographic and cardiovascular factors. We found that individuals with hearing impairment (n=51) compared to those with normal hearing (n=75) had accelerated volume declines in whole brain and regional volumes in the right temporal lobe (superior, middle, and inferior temporal gyri, parahippocampus, p<.05). These results were robust to adjustment for multiple confounders and were consistent with voxel-based analyses, which also implicated right greater than left temporal regions. These findings demonstrate that peripheral hearing impairment is independently associated with accelerated brain atrophy in whole brain and regional volumes concentrated in the right temporal lobe. Further studies investigating the mechanistic basis of the observed associations are needed.

Serum protein signatures detect early radiographic osteoarthritis.

OBJECTIVE: To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident. METHODS: Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques. RESULTS: Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA. CONCLUSIONS: Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

Sex hormone binding globulin levels across the adult lifespan in women--the role of body mass index and fasting insulin.

SHBG is a major carrier of androgens. In men, SHBG levels increase with age, while in women data are scant. There is evidence that body mass index (BMI) and fasting insulin influence SHBG concentration. Since low SHBG levels are predictors of insulin resistance and diabetes, understanding the relationship of SHBG with age, insulin, and BMI is important to gain insight into the role of SHBG as a cardiovascular risk factor in women. Differences in SHBG across adult life span and their relationship with insulin and BMI were evaluated in a representative cohort of 616 Italian women free of diabetes and not on hormone replacement therapy enrolled in the InCHIANTI Study. The relationship of SHBG with age, BMI, and fasting insulin levels was analyzed using linear regression and by loess smoother. Serum SHBG levels showed a U-shaped trajectory with age, declining from the 2nd to the 6th decade of life and increasing after the 6th decade (p<0.0001). Age-related trends for BMI and fasting insulin mirrored the trend observed for SHBG. After adjusting for fasting insulin, the relationship between log (SHBG) and age square was attenuated (beta coefficient from 0.00044 to 0.00039) and was further reduced after adjustment for BMI (from 0.00039 to 0.00028). SHBG levels show an age-related U-shaped trajectory. These changes mirror the age-related changes in BMI and fasting insulin, suggesting that BMI and insulin negatively influence SHBG concentration.

Prostate-specific antigen testing of older men.

BACKGROUND: Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection. METHODS: We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age. RESULTS: All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%-100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%-100%) of the cancers would still be detected by age 75 years. CONCLUSIONS: These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.

Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.

Prostate growth curves were estimated from serial prostate-specific antigen (PSA) measurements on frozen sera in three groups of men: (a) 16 men with no prostatic disease by urological history and examination; (b) 20 men with a histological diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and (c) 18 men with a histological diagnosis of prostate cancer. The median number of repeated PSA measurements over an 8- to 26-yr period prior to histological diagnosis or exclusion of prostate disease was eight and 11 for noncancer and cancer subjects, respectively. Predicted rates of change in PSA (PSA velocity) were linear and curvilinear for control and BPH subjects, respectively. Subjects with cancer demonstrated both a linear and an exponential phase of PSA velocity. Based on time to double PSA, we estimated the epithelial doubling time for men without prostate disease to range from 54 +/- 13 yr at age 40 to 84 +/- 13 yr at age 70. For men with BPH, doubling times ranged from 2 +/- 13 yr at age 40 to 17 +/- 5 yr at age 85. Subjects with local/regional and advanced/metastatic cancer had similar PSA doubling times of 2.4 +/- 0.6 yr and 1.8 +/- 0.2 yr, respectively. These data are consistent with what is known about prostatic growth with age in men without prostate disease and BPH, and the kinetics of prostate cancer growth. Estimates of prostatic growth rate from changes in PSA may be useful clinically in management of men with prostate disease.

Cerebral glucose metabolic patterns in Alzheimer's disease. Effect of gender and age at dementia onset.

No previous study of Alzheimer's disease has, to our knowledge, assessed the effect of both age at dementia onset and gender on cerebral glucose metabolic patterns. To this end, we used positron emission tomography (fludeoxyglucose F 18 method) to study 24 patients with clinical diagnoses of probable Alzheimer's disease. Comparisons of the 13 patients with early-onset dementia (less than 65 years of age) with the 11 patients with late-onset dementia (greater than 65 years of age) revealed significantly lower left parietal metabolic ratios (left posterior parietal region divided by the hemispheric average) in the early-onset group. The metabolic ratio of posterior parietal cortex divided by the relatively disease-stable average of caudate and thalamus also separated patients with early-onset dementia from those with late-onset dementia, but not men from women. Further comparisons between sexes showed that, in all brain regions studied, the 9 postmenopausal women had higher nonweighted mean metabolic rates than the 15 men from the same age group, with hemispheric sex differences of 9% on the right and 7% on the left. These results demonstrate decreased parietal ratios in early-onset dementia of Alzheimer's disease, independent of a gender effect.

Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women.

OBJECTIVE: This study examines the influence of age and current estrogen replacement therapy (ERT) on common carotid arterial (CCA) stiffness in women. METHODS: The subjects comprised 172 women (age 55.6 +/- 16.4 years) from the Baltimore Longitudinal Study of Aging, including 37 current postmenopausal ERT users. The ERT users included 18 women taking estrogen alone and 19 women taking estrogen and progesterone. Bilateral CCA were examined by B-mode carotid ultrasonography, and the stiffness index was defined as the logarithm of the ratio of systolic to diastolic blood pressure (BP) divided by the fractional diameter increase during the cardiac cycle. RESULTS: The stiffness index increased linearly with age (r = 0.69, p < 0.001), and was lower in ERT users than in postmenopausal nonusers (8.0 +/- 2.0 vs 9.7 +/- 3.1, p < 0.01). Furthermore, the effects of age (beta = 0.67, p < 0.0001) and ERT (beta = -0.23, p < 0.001) on the stiffness index persisted after adjustments for systolic BP (beta = 0.23, p < 0.01), diastolic BP (beta = -0.26, p < 0.001) and other cardiovascular risk factors (model r2 = 0.59, p < 0.0001). The stiffness index was similar in both ERT users with and without progesterone and lower than in postmenopausal nonusers (p < 0.05) after considering the age effects. CONCLUSION: Age-associated increases in CCA stiffness are reduced by postmenopausal ERT.

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer.

Insulin-like growth factors (IGFs) may play a role in prostate growth, hyperplasia, and malignancy. High plasma IGF-I has been associated with increased prostate cancer risk. In a prospective, cohort, case-control study in the Baltimore Longitudinal Study on Aging population, we examined prostate volume by magnetic resonance imaging, and prostate-specific antigen (PSA), IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in sera obtained approximately 9 yr before diagnosis of prostate cancer in cases (n = 72) or age-matched controls (n = 127) and in 76 additional Baltimore Longitudinal Study on Aging men (normal subjects) with measured prostate volumes and no prostate cancer. We calculated adjusted odds ratios (OR) by logistic regression, relative risks for significant ORs, and receiver operator curves for prostate cancer, using serum measures alone and in combination. Adjusted ORs for the high vs. low tertile were: for IGF-I, 3.1 [confidence interval (CI), 1.1-8.7]; for IGF-II, 0.2 (CI, 0.07-0.6); for IGFBP-3, 0.71 (CI, 0.3-1.7); and for PSA, 12.5 (CI, 3.8-40.9). For significant ORs, relative risk estimates remained significant at 2.0 for IGF-I, 0.3 for IGF-II, and 5.5 for PSA. Receiver operator curves showed PSA to be the most powerful predictor of prostate cancer. Adding IGF-II to PSA improved prediction. IGF-II was significantly and inversely related (r = -0.219; P < 0.01) and PSA was directly and significantly related (r = 0.461; P < 0.0001) to prostate volume, whereas IGF-I and IBFBP-3 were not. High IGF-I and low IGF-II are independently associated with increased risk of prostate cancer, but PSA level is a much stronger predictor of prostate cancer in the ensuing 10 yr than either IGF-I or IGF-II. The absence of a relationship of IGF-I to prostate size is inconsistent with increased ascertainment in men with large prostates as the source of greater prostate cancer risk associated with IGF-I. Our data suggest that IGF-II may inhibit both prostate growth and development of prostate cancer.

Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging.

Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.

Cerebral metabolic relationships for selected brain regions in healthy adults.

The local cerebral metabolic rate for glucose was determined in 26 regions of the brain in 31 healthy subjects who underwent resting fluorodeoxyglucose positron emission tomography. Intercorrelations among the 26 regional measures were accepted as reliable at p less than 0.01 (r greater than 0.45), uncorrected for the number of measures. From the matrix two apparently separate functional metabolic systems were identified: (1) a superior system involving the superior and middle frontal gyri, the inferior parietal lobule, and the occipital cortex; and (2) an inferior system involving the inferior frontal, Broca's, and posterior temporal regions. Evidence is presented to suggest that the superior system is involved in visual processing, memory recognition, and decision making, while the inferior system seems to at least participate in language-related functions.

Cerebral metabolic relationships for selected brain regions in Alzheimer's, Huntington's, and Parkinson's diseases.

Local CMRGlc values were determined for 13 regions in each hemisphere from tomographs of patients with Alzheimer's, Huntington's, and Parkinson's diseases who were studied using [18F]fluorodeoxyglucose with positron emission computed tomography. Intercorrelations among the 26 regional measures were calculated for each disease state and for normal controls, and were accepted as reliable at p less than 0.01, uncorrected for the number of comparisons. The number of reliable correlations was found to be decreased in Parkinson's and Huntington's diseases, two primarily subcortical disorders, and increased in Alzheimer's disease, a primarily cortical disorder. The changes suggest that one role of the basal ganglia involves coordinating or pacing the ability of cortical brain regions to function as a unit.

Effects of human aging on patterns of local cerebral glucose utilization determined by the [18F]fluorodeoxyglucose method.

The [18F]fluorodeoxyglucose (FDG) scan method with positron emission computed tomography was used to determine patterns of local cerebral glucose utilization (LCMRglu) in 40 normal volunteer subjects aged 18 to 78 years. Throughout all the studies, each subject was quiet, without movement, with eyes open and ears unplugged, exposed only to ambient room light and sound. For the entire group, whole brain mean CMRglu was 26.1 +/- 6.1 mumol 100 g-1 min-1 (mean +/- SD, n = 40). At age 78, mean CMRglu was, on the average, 26% less than at age 18, an alteration of the same order as the variance among subjects at any age. The gradual decline of mean CMRglu with advancing age occurred at a faster rate than was reported for mean cerebral oxygen utilization, possibly due to increasingly altered pathways for glucose utilization, or to increasing oxidation of ketone bodies or other alternative substrates. Glucose utilization in the hemispheres was symmetrical and mean CMRglu of overall cortex, caudate, and thalamus was equal in individuals at all ages. The slopes of decline with age were similar when LCMRglu was averaged over zones corresponding to centrum semiovale, caudate, putamen, and frontal, temporal, parietal, occipital, and primary visual cortex. However, the metabolic ratio of superior frontal cortex to superior parietal cortex declined with age, possibly due to selective degeneration of superior frontal cortex or to differences between age groups in the sensory and cognitive response to the study. These results should be useful in distinguishing age from disease effects when the FDG scan method is used.

Cerebral glucose metabolism as a function of age in man: influence of the rate constants in the fluorodeoxyglucose method.

Measurement of the local cerebral metabolic rate of glucose (LCMRGlc) with the fluorodeoxyglucose (FDG) method requires the utilization of appropriate values for the rate constants of the transport and phosphorylation processes. We measured these rate constants as a function of age to determine whether a decline in LCMRGlc as a function of age, in prior studies with the FDG method, actually represents changes in the rate constants. We found that measurements of LCMRGlc are not significantly affected by changes in rate constants as a function of aging, and that LCMRGlc did not change significantly with age.

Cognitive and brain imaging measures of Alzheimer's disease.

Diagnosis of Alzheimer's disease (AD) during life relies upon clinical and neurobehavioral symptoms but is presumptive without microscopic verification of neuropathology. Studies in this review observed considerable heterogeneity in AD symptoms and did not agree on how to detect the earliest symptoms. Problems exist in diagnosis. Differences in symptoms and diagnosis result from how AD is defined neurobehaviorally and on the model used for description. The studies reviewed have been considered under three basic models: A severity (staging) model; a heterogeneity (subtyping) model; and an information processing model. Differences in model intent have resulted in differences in disease description. Brain imaging measures have not invalidated models but add the neural substrate needed to examine correlation of measures within each model.

Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function.

This study investigates the age associated changes in hemorheological properties and cerebral blood flow. Partial correlations indicate that part of the age-dependent decrease in flow velocities can be attributed to a hemorheological decrement resulting in part from enhanced oxidative stress in the aged. A possible link with Alzheimer's pathology is suggested by the augmented hemorheological impairment resulting from in vitro incubation of red cells with amyloids. These results suggest that in aging, oxidative stress as well as amyloids may influence the fluid properties of blood, resulting in a potential decrement in blood flow and oxygen delivery to the brain. Animal intervention studies further demonstrate that altered hemorheological properties of blood can actually influence cognitive function. The relationships shown to exist between hemorheology, blood flow, amyloids, oxidative stress, and cognitive function suggest that these factors may be one of the mechanisms operating in the complex etiology of Alzheimer's disease.

Comparison of PET measurement of local brain glucose metabolism and CAT measurement of brain atrophy in chronic schizophrenia and depression.

Using [18F]fluorodeoxyglucose and positron emission tomography (PET), the authors examined the regional brain glucose metabolism of six patients with chronic schizophrenia, six patients with chronic depression, and 12 normal control subjects. Three schizophrenic and four depressive patients had CAT scans that showed enlarged ventricles (ventricle-brain ratios higher than 9.0) and widened sylvian fissures. The PET scans of the schizophrenic and depressed patients did not differ significantly from those of the age-matched controls, and a previously reported metabolic "hypofrontality" was not confirmed. The patients with enlarged ventricles and widened sylvian fissures tended to have lower global metabolism.

Cerebral glucose metabolism in Wernicke's, Broca's, and conduction aphasia.

Cerebral glucose metabolism was evaluated in patients with either Wernicke's (N = 7), Broca's (N = 11), or conduction (N = 10) aphasia using 18F-2-fluoro-2-deoxy-D-glucose with positron emission tomography. The three aphasic syndromes differed in the degree of left-to-right frontal metabolic asymmetry, with Broca's aphasia showing severe asymmetry and Wernicke's aphasia mild-to-moderate metabolic asymmetry, while patients with conduction aphasia were metabolically symmetric. On the other hand, the three syndromes showed the same degree of metabolic decline in the left temporal region. The parietal region appeared to separate conduction aphasia from both Broca's and Wernicke's aphasias. Common aphasic features in the three syndromes appear to be due to common changes in the temporal region, while unique features were associated with frontal and parietal metabolic differences.

Subcortical structures in aphasia. An analysis based on (F-18)-fluorodeoxyglucose, positron emission tomography, and computed tomography.

Subcortical structural damage that includes the anterior and posterior internal capsule, caudate, thalamus, lenticular nuclei, and insula has been shown to cause aphasias. A critical question that has not been resolved is whether the role of these structures on behavior is a direct one or whether it is indirect through the cortex. We have used pathway analysis to evaluate computed tomography, glucose metabolic, and language data from 47 aphasic patients to answer this question. For fluency (from the Western Aphasia Battery), subcortical structural damage had direct and indirect (through frontal lobe) effects on the behavior. For a comprehension task (sequential commands), subcortical damage had no direct effect and only a slight indirect effect through the temporal lobe. Thus, both direct and indirect effects of subcortical damage can be demonstrated for specific behavioral measures.

Disconnection and cerebral metabolism. The case of conduction aphasia.

Ten patients with conduction aphasia were studied with computed tomography and 18-F-fluorodeoxyglucose positron emission tomography to examine glucose metabolism. Computed tomographic results identified a postrolandic structural locus for conduction aphasia. All patients demonstrated resting glucose hypometabolism throughout the parietal and temporal regions, and half of the patients also demonstrated reduced metabolic rates in the posterior, inferior, frontal (Broca's) regions. These data suggest that disconnection between posterior and anterior language areas may not be the best anatomical explanation for conduction aphasia.

Temporoparietal cortex in aphasia. Evidence from positron emission tomography.

Forty-four aphasic patients were examined with (F18)-fluorodeoxyglucose positron emission tomography in a resting state to determine whether consistent glucose metabolic abnormalities were present. Ninety-seven percent of subjects showed metabolic abnormalities in the angular gyrus, 89% in the supramarginal gyrus, and 87% in the lateral and transverse superior temporal gyrus. Pearson product moment correlations were calculated between regional metabolic measures and performance on the Western Aphasia Battery. No significant correlations were found between the Western Aphasia Battery scores and right hemisphere metabolic measures. Most left hemisphere regions correlated with more than one score from the Western Aphasia Battery. Temporal but not frontal regions had significant correlations to the comprehension score. The left temporoparietal region was consistently affected in these subjects, suggesting that common features in the aphasias were caused by left temporoparietal dysfunction, while behavioral differences resulted from (1) the extent of temporoparietal changes, and (2) dysfunction elsewhere in the brain, particularly the left frontal and subcortical areas.