Takahashi, Paul

Background and Purpose: Stroke is a well-known risk factor for vascular dementia. However, the association of transient ischemic attacks with cognitive impairment is less well-established. Methods: Records from Third National Health and Nutrition Examination Survey were abstracted for demographic and medical information for participants with an age !60 years who reported being free of stroke. Five self-reported symptoms (weakness, numbness, loss of vision, inability to speak, and severe dizziness) were used as surrogates representing transient ischemic attacks. Information on conventional risk factors for vascular dementia was also obtained. Multivariable logistic regression was used to examine risk factors for memory impairment. Results: 4617 participants were included with a sample-weighted prevalence of memory impairment of 6.6% (1417 participants). The final multivariable analysis revealed a significant association between transient weakness and memory impairment (odds ratio 1.52, 95% CI 1.11-2.07). The other 4 transient ischemic attacks symptoms were not significantly associated with memory impairment in the final model. Systolic blood pressure >140 was most strongly associated with prevalent memory impairment (odds ratio, 9.78, 95% CI 1.49-64.3). Other associated risk factors included non-white race, male gender, age, education ≤12 years, and history of any alcohol use. Conclusion: Among transient ischemic attacks symptoms, self-reported weakness in the face, arm, or leg was significantly associated with memory impairment. This study indicates that transient ischemic attacks symptoms are, even in the absence of stroke, associated with memory impairment. Aggressive risk factor modification in patients with TIA symptoms may be warranted to prevent potential future memory loss.

The purpose of this study was to assess whether the relationship between obesity and use of medical visits is different for geriatric patients than for other adults. A retrospective analysis was conducted using medical records drawn from a large group practice in Rochester, Minnesota. Adult patients ( n = 1715) were sorted into 2 groups (frequent visitors and others). Separate multiple logistic regression models were estimated for geriatric and non-geriatric patients. Patients who were 65 years of age or older with moderate comorbidity had elevated odds of being frequent visitors (odds ratio [OR] = 6.13, confidence interval [CI] = 3.27–11.49), compared to patients with no comorbidity. Body mass index (BMI), gender, and marital status were unrelated to visit frequency in the geriatric group. Younger patients with a BMI ≥ 35 kg/m 2 had greater odds of being frequent visitors compared to patients with normal body mass, after adjusting for comorbidity, age, marital status, and gender (OR = 1.96, CI = 1.31–2.92). ORs also were significantly greater for subjects with low (OR = 2.13, CI = 1.51–3.01) and moderate comorbidity (OR = 3.32, CI = 2.32–4.76) versus no comorbidity. In our sample of family medicine patients who were referred to specialists, BMI ≥ 35 kg/m 2 is an independent risk factor for frequent utilization of medical visits among adults who are younger than age 65, but not among geriatric patients. Comorbidity is strongly related to visit frequency among both older and younger adult patients. (Population Health Management 2008;11:255–259)

Abstract Context: Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus, and/or pituitary gland is unknown. Objective: Our objective was to quantify the impact of age on gonadal Te secretion driven by amplitude-varying pulses of recombinant human LH (rhLH) in the absence of confounding by endogenous hypothalamo-pituitary signals. Design: This was a double-blind, placebo-controlled study. Setting: The setting was an academic medical center. Subjects: Fifteen healthy community-dwelling men ages 22–78 yr were included in the study. Intervention: Saline or four separate rhLH doses were each infused twice iv in randomized order as one pulse every 2 h over 20 h to stimulate Te secretion, after LH secretion was suppressed by a GnRH-receptor antagonist, ganirelix. Main Outcome: LH and Te concentrations were determined in blood samples collected every 5 min. Maximal and minimal (as well as mean) Te responses were regressed linearly on age to reflect LH peak and nadir (and average) effects, respectively. Results: The ganirelix/rhLH paradigm yielded serum LH concentrations of 4.6 ± 0.22 IU/liter (normal range 1–9). By regression analysis, age was associated with declines in rhLH pulse-stimulated peak and nadir (and mean) concentrations of total Te (P = 0.0068), bioavailable Te (P = 0.0096), and free Te (P = 0.013), as well as lower Te/LH concentration ratios (P < 0.005). Deconvolution analysis suggested that the half-life of infused LH increases by 12%/decade (P = 0.044; R2 = 0.28). Conclusions: Infusion of amplitude-varying pulses of rhLH during gonadal-axis suppression in healthy men unmasks prominent age-related deficits in stimulated total (39%), bioavailable (66%), and free (63%) Te concentrations, and a smaller age-associated increase in LH half-life. These data suggest that age-associated factors reduce the efficacy of LH pulses.

Abstract Background: Healthy older men have reduced testosterone (Te) production and frequent, small irregular LH pulses. Which is cause and which is effect are not known. Rationale: In model systems, frequent and irregular LH pulses reflect attenuated feedback inhibition by Te. Hypothesis: Factors associated with aging impair negative feedback by Te. Subjects and Setting: Healthy men at an academic medical center were studied. Methods: The study used quantification of the regularity of LH release patterns during blockade of gonadal steroidogenesis and graded transdermal Te addback in 18 healthy men aged 18–65 yr. Results: In the cohort as a whole, stepwise Te repletion repressed LH concentrations (P = 0.001) and enhanced the quantifiable orderliness of LH release patterns (P < 0.001). By regression analysis, age attenuated the capability of increasing Te concentrations to regularize LH secretion patterns (P = 0.019). However, after a fixed GnRH stimulus, the effect of Te on LH regularity was invariant of the age factor (P = 0.16), thus pointing to a hypothalamic locus of impaired Te feedback. Summary: Aging disrupts the capability of systemic Te concentrations to maintain orderly LH secretion under endogenous, but not exogenous, GnRH drive. Conclusions: Age or factors associated with increased age reduce negative feedback by any given total Te concentration on hypothalamopituitary GnRH-LH outflow, thus contributing to disorderly LH secretion.

Context: Testosterone (Te) depletion in aging men in principle could reflect deficits in the hypothalamus, pituitary gland, or testis. Available pharmacological studies of possible failure of Leydig cell steroidogenesis remain inconclusive. Objective: The objective of the study was to assess Te secretion in older and young men in response to near physiological LH stimulation. Intervention: Pulsatile iv infusion of recombinant human LH was administered for 2 d to stimulate Te secretion during suppression of endogenous LH concentrations with a potent selective GnRH receptor antagonist (ganirelix). Subjects/Context: Healthy older (aged 60–73 yr, n = 8) and young (19–30 yr, n = 13) men were studied in an academic setting. Measures: Pulsatile LH and Te concentrations on the second day of exogenous LH stimulation were measured. Results: Serum ganirelix concentrations and infused LH pulse increments were similar by age. In contrast, older subjects manifested: 1) reduced mean Te concentrations (P = 0.016), Te peak heights (P = 0.014), increments (P = 0.010), summed areas (P < 0.013), and interpeak Te concentrations (P = 0.023); 2) decreased Te to LH concentration ratios (P = 0.002); 3) diminished LH-Te feed-forward synchrony (P = 0.020); and 4) a blunted amplitude (P = 0.036) and advanced phase (P = 0.013) of diurnal Te rhythms. Conclusion: A novel regimen of pulsatile LH stimulation for 48 h during GnRH receptor blockade unmasks deficits in pulsatile, basal, synchronous, and nyctohemeral Te secretion in healthy older men. These findings do not exclude concomitant defects in GnRH outflow and/or Te-negative feedback in the aging male.

Healthy older men manifest concomitant hypoandrogenemia and attenuation of LH pulse size. Because exogenous GnRH remains effective, a plausible intuition is that aging reduces hypothalamic GnRH secretion, thus mediating relative hypogonadotropic hypogonadism. To assess the impact of age on central GnRH outflow indirectly, we quantitated graded suppression of pulsatile LH secretion by saline and escalating doses of a potent and selective GnRH-receptor antagonist, ganirelix, in 18 healthy men ages 23–72 yr. The rationale is that ganirelix should reduce the amplitude of LH pulses in proportion to both drug concentration and endogenous GnRH feedforward. To this end, blood was sampled every 10 min for 2 h before and 16 h after sc administration of saline or ganirelix and for 3 additional hours after iv injection of a fixed dose of GnRH (100 ng/kg); concentrations of LH and ganirelix were measured by immunochemiluminometry and RIA, respectively; and pulsatile LH secretion was quantitated by a deconvolution procedure. Log-linear regression analysis was used to estimate the sensitivity of pulsatile LH secretion to inhibition by a unit increase in serum ganirelix concentrations in each subject. Statistical analyses revealed that increasing age markedly attenuated the capability of ganirelix to decrease LH pulse size (viz., r = −0.648; P = 0.004). In contrast, age did not modify the competitive interaction between injected GnRH and ganirelix. These joint outcomes support the clinical hypothesis that age diminishes hypothalamic GnRH outflow without impairing GnRH action in healthy men.