Memory impairment in aged primates is associated with region-specific network dysfunction.

Age-related deficits in episodic memory result, in part, from declines in the integrity of medial temporal lobe structures, such as the hippocampus, but are not thought to be due to widespread loss of principal neurons. Studies in rodents suggest, however, that inhibitory interneurons may be particularly vulnerable in advanced age. Optimal encoding and retrieval of information depend on a balance of excitatory and inhibitory transmission. It is not known whether a disruption of this balance is observed in aging non-human primates, and whether such changes affect network function and behavior. To examine this question, we combine large-scale electrophysiological recordings with cell-type-specific imaging in the medial temporal lobe of cognitively assessed, aged rhesus macaques. We found that neuron excitability in the hippocampal region CA3 is negatively correlated with the density of somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in the stratum oriens. By contrast, no hyperexcitability or interneuron loss was observed in the perirhinal cortex of these aged, memory-impaired monkeys. These data provide a link, for the first time, between selective increases in principal cell excitability and declines in a molecularly defined population of interneurons that regulate network inhibition.

Distinguishing adaptive plasticity from vulnerability in the aging hippocampus.

Hippocampal circuits are among the best described networks in the mammalian brain, particularly with regard to the alterations that arise during normal aging. Decades of research indicate multiple points of vulnerability in aging neural circuits, and it has been proposed that each of these changes make a contribution to observed age-related cognitive deficits. Another view has been relatively overlooked - namely that some of these changes arise in adaptive response to protect network function in aged animals. This possibility leads to a rather different view on the biological variation of function in the brain of older individuals. Using the hippocampus as a model neural circuit we discuss how, in normally aged animals, some age-related changes may arise through processes of neural plasticity that serve to enhance network function rather than to hinder it. Conceptually disentangling the initial age-related vulnerabilities from changes that result in adaptive response will be a major challenge for the future research on brain aging. We suggest that a reformulation of how normal aging could be understood from an adaptive perspective will lead to a deeper understanding of the secrets behind successful brain aging and our recent cultural successes in facilitating these processes.

Regional and age-related differences in GAD67 expression of parvalbumin- and calbindin-expressing neurons in the rhesus macaque auditory midbrain and brainstem.

Neurons expressing the calcium binding proteins (CaBPs) parvalbumin (PV) and calbindin (CB) have shown age-related density changes throughout the ascending auditory system of both rodents and macaque monkeys. In the cerebral cortex, neurons expressing these CaBPs express markers of γ-aminobutyric acidergic neurotransmission, such as GAD67, and have well-understood physiological response properties. Recent evidence suggests that, in the rodent auditory brainstem, CaBP-containing cells do not express GAD67. It is unknown whether PV- and CB-containing cells in subcortical auditory structures of macaques similarly do not express GAD67, and a better understanding of the neurotransmission of neurons expressing these proteins is necessary for understanding the age-related changes in their density throughout the macaque auditory system. This was investigated with immunofluorescent double-labeling techniques to coregister PV- and CB-expressing neurons with GAD67 in the superior olivary complex and the inferior colliculus of young and aged rhesus macaques. The proportions of GAD67-expressing PV- and CB-positive neurons were computed with unbiased sampling techniques. Our results indicate that between 42% and 62% of PV- and CB-positive neurons in the auditory brainstem and midbrain express GAD67, which is significantly less than in the cerebrum. In general, fewer PV(+) neurons and more CB(+) neurons expressed GAD67 as a function of age. These results demonstrate that the inhibitory molecular profile of PV- and CB-expressing neurons can change with age in subcortical auditory structures and that these neurons are distinct from the well-described inhibitory interneurons that express these proteins in the cerebral cortex.

Probability of filtration surgery in patients with open-angle glaucoma.

OBJECTIVE: To investigate the probability of undergoing filtration surgery in either 1 or both eyes in patients in whom open-angle glaucoma was newly diagnosed. METHODS AND DESIGN: A retrospective community-based study of 295 residents of Olmsted County, Minnesota, in whom open-angle glaucoma was newly diagnosed between January 1, 1965, and December 31, 1980, was performed. Kaplan-Meier methods were used to estimate the cumulative probability of undergoing filtration surgery during a 20-year period. RESULTS: At 20 years of follow-up, the Kaplan-Meier cumulative probability of undergoing filtration surgery in at least 1 eye was estimated to be 23% (95% confidence interval, 16%-30%), and in both eyes the estimate was 12% (95% confidence interval, 6%-17%). Patients with optic nerve damage at the time of diagnosis were more likely to undergo surgery than patients with elevated intraocular pressure but no damage (1 eye, 39% vs 15%; both eyes, 27% vs 5%). CONCLUSION: This retrospective study of a white population newly diagnosed as having and treated for open-angle glaucoma indicates that while most patients did not undergo filtration surgery in the course of glaucoma therapy, at least one third of those with glaucomatous damage at the time of diagnosis underwent filtration surgery.

Pediatric third, fourth, and sixth nerve palsies: a population-based study.

PURPOSE: To determine the population-based incidence and cause of cranial nerve palsies affecting ocular motility in children in the circumscribed population of Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project medical records linkage system captures virtually all medical care provided to Olmsted County residents. By means of this database, all cases of third, fourth, and sixth cranial nerve palsy were identified among county residents less than 18 years of age from 1978 through 1992. Medical records were reviewed to confirm the diagnosis, determine the cause, and document county residency. Incidence rates were adjusted to the age and sex distribution of the 1990 white population in the United States. RESULTS: Over this 15-year period, 36 incidence cases of cranial nerve palsy were identified in 35 children in this defined population. The age-adjusted and sex-adjusted annual incidence of third, fourth, and sixth nerve palsies combined was 7.6 per 100,000 (95% confidence interval, 5.1 to 10.1). The most commonly affected nerve was the fourth (36%), followed by the sixth (33%), the third (22%), and multiple nerve palsies (9%). The most common cause was congenital for third and fourth nerve palsy, undetermined for sixth, and trauma for multiple nerve palsies. Although three cases were associated with neoplasia, a cranial nerve palsy was not present at the time of diagnosis in any case. CONCLUSIONS: Unlike many institutionally based referral series, our population-based study provides data on the incidence and cause of third, fourth, and sixth nerve palsies in a geographically defined population. In contrast to previous institutionally based series, nearly half the cases were congenital in origin, and in no case did intracranial neoplasia present as an isolated nerve palsy.

Retinal detachment in Olmsted County, Minnesota, 1976 through 1995.

OBJECTIVE: To estimate the incidence of rhegmatogenous retinal detachment (RD) in a geographically defined population and to compare the probability of RD in residents after cataract extraction with the probability of RD in residents who did not have cataract extraction. DESIGN: Rochester Epidemiology Project databases were used to perform a retrospective population-based incidence study of RD diagnosed between 1976 and 1995 with cohort analyses of the influence of risk factors on the occurrence of RD. PARTICIPANTS: The population of Olmsted County, Minnesota, participated. MAIN OUTCOME MEASURE: Incidence rates of RD adjusted to the age and gender distribution of the 1990 U.S. white population were measured. RESULTS: Three hundred eleven incident cases of rhegmatogenous RD were identified. The mean annual age- and gender-adjusted incidence rate of rhegmatogenous RD was 17.9 per 100,000 persons (95% confidence interval [CI], 15.9-19.9). For idiopathic rhegmatogenous RD alone, the mean annual age- and gender-adjusted incidence rate was 12.6 (95% CI, 10.9-14.3) per 100,000 persons. Ten years after phacoemulsification and extracapsular cataract extraction, the estimated cumulative probability of RD was 5.5 (95% CI, 3.4-7.6) times as high as would have been expected in a similar group of county residents not undergoing cataract surgery. CONCLUSIONS: Cataract surgery is associated with a significantly elevated long-term cumulative probability of retinal detachment.

The probability of blindness from open-angle glaucoma.

OBJECTIVE: This study aimed to determine the probability of a patient developing legal blindness in either one or both eyes from newly diagnosed and treated open-angle glaucoma (OAG) after starting medical or surgical therapy or both. DESIGN: The study design was a retrospective, community-based descriptive study. PARTICIPANTS: Two hundred ninety-five residents of Olmsted County, Minnesota, newly diagnosed with, and treated for, OAG between 1965 and 1980 with a mean follow-up of 15 years (standard deviation +/- 8 years) participated. INTERVENTION: Kaplan-Meier cumulative probability of blindness was estimated for patients treated and followed for OAG. MAIN OUTCOME MEASURES: Legal blindness, defined as a corrected visual acuity of 20/200 or worse, and/or visual field constricted to 20 degrees or less in its widest diameter with the Goldmann 1114e test object or its equivalent on automated perimetry, secondary to glaucomatous loss, was measured. RESULTS: At 20-years' follow-up, the Kaplan-Meier cumulative probability of glaucoma-related blindness in at least one eye was estimated to be 27% (95% confidence interval, 20%-33%), and for both eyes, it was estimated to be 9% (95% confidence interval, 5%-14%). At the time of diagnosis, 15 patients were blind in at least 1 eye from OAG. CONCLUSION: A retrospective study of a white population determined that the risk of blindness from newly diagnosed and treated OAG may be considerable.

Outcomes of anesthesia and surgery in people 100 years of age and older.

OBJECTIVE: To assess the outcomes of anesthesia and surgery for men and women 100 years of age and older. DESIGN: Retrospective cohort study in the 20-year time period from 1975 to 1994, with follow-up through 1995. SETTING: Mayo-affiliated hospitals and Olmsted Community Hospital, Rochester, Minnesota. PARTICIPANTS: All men and women 100 years of age and older who underwent surgery at a participating hospital. MEASUREMENTS: Forty-eight-hour and 30-day perioperative morbidity and mortality; long-term survival. RESULTS: Thirty-one men and women aged 100 to 107 years underwent 42 procedures. One major complication (3%) within 48 hours was observed. The 48-hour, 30-day, and 1-year mortality rates were 0%, 16.1%, and 35.5%, respectively. When compared with survival rates for age-, gender-, and calendar year of birth-matched peers from the general population, the survival rate for centenarians who underwent surgery and anesthesia was comparable to the rate expected. CONCLUSION: These data suggest that people 100 years of age and older who have operable diseases or injuries should not be denied surgical interventions because of perceived risks associated with their advanced age.

Decision and cost-utility analyses of surgical versus transcatheter closure of patent ductus arteriosus: should you let a smile be your umbrella?

Decision and cost-utility analyses considered the tradeoffs of treating patent ductus arteriosus (PDA) using conventional surgery versus transcatheter implantation of the Rashkind occluder. Physicians and informed lay parents assigned utility scores to procedure success/complications combinations seen in prognostically similar pediatric patients with isolated PDA treated from 1982 to 1987. Utility scores multiplied by outcome frequencies from a comparative study generated expected utility values for the two approaches. Cost-utility analyses combined these results with simulated provider cost estimates from 1989. On a 0-100 scale (worst to best observed outcome), the median expected utility for surgery was 99.96, versus 98.88 for the occluder. Results of most sensitivity analyses also slightly favored surgery. Expected utility differences based on 1987 data were minimal. With a mean overall simulated cost of $8,838 vs $12,466 for the occluder, surgery was favored in most cost-utility analyses. Use of the inherently less invasive but less successful, more risky, and more costly occluder approach conferred no apparent net advantage in this study. Analyses of comparable current data would be informative.

Prognostic value of exercise thallium-201 imaging in a community population.

BACKGROUND: The prognostic value of exercise thallium-201 imaging has been well established in referral patient populations at tertiary care centers, but these results may be influenced by referral bias. METHODS: This study was performed to evaluate the prognostic value of thallium imaging in a community-based population of 446 residents of Olmsted County, Minn. Eleven variables were prospectively selected and tested for their associations with outcome end points. RESULTS: Four variables (age, history of myocardial infarction, number of abnormal thallium segments on the postexercise images, and increased thallium lung uptake) contained the most independent prognostic information. For the end point overall mortality rate, the multivariate chi-square values were 17.2 (p < 0.0001) for age and 20.9 (p < 0.0001) for the number of abnormal thallium segments on the postexercise images. Five-year survival rate for patients older than the median age of 59 years with an abnormal scan was 84% versus 97% for patients < or = 59 years of age with a normal scan. CONCLUSION: Exercise thallium imaging was useful for prognostic purposes in this relatively low-risk community population, confirming the findings of referral population studies.

Cataract extraction rates in Olmsted County, Minnesota, 1980 through 1994.

OBJECTIVE: To analyze population-based trends in cataract extraction. DESIGN: Rochester Epidemiology Project databases; which capture virtually all health care services provided to residents of Olmsted County, Minnesota, were used to perform retrospective cohort analyses of rates of primary cataract extractions performed between 1980 and 1994. PARTICIPANTS: The population of Olmsted County, Minnesota. MAIN OUTCOME MEASURES: Incidence rates adjusted to the age and sex distribution of the 1990 US white population were analyzed using Poisson regression. RESULTS: The 4257 procedures performed on 3176 patients of all ages represented overall annual age-adjusted rates of 404 procedures per 100,000 females and 320 per 100,000 males. Annual age- and sex-adjusted rates for both sexes combined rose from 133 procedures per 100,000 in 1980 to a peak of 507 per 100,000 in 1992. The rates fell to 470 per 100,000 in 1994. Manual review of a random sample of records estimated case overascertainment at 0.9%. CONCLUSIONS: With the exception of 1988 and 1989, rates of cataract surgery in this geographically circumscribed population increased every year between 1980 and 1992. Data from 1993-1994 indicate that rates may have plateaued and possibly declined slightly. If sustained, these patterns could have major implications for future utilization of ophthalmologic resources.

Concordance of Medicare data and population-based clinical data on cataract surgery utilization in Olmsted County, Minnesota.

The authors assessed concordance of local Medicare health care utilization data on cataract surgery and estimates generated using the databases of the Rochester Epidemiology Project, which capture virtually all medical care received by residents of Olmsted County, Minnesota. The Rochester Project databases identified 1,353 primary cataract extractions performed in Olmsted County between October 1989 and December 1993 among county residents aged > or = 65 years. Medicare data identified 1,148 claims-84.8% of the number of procedures identified by the Rochester Project. Ratios of numbers of encounters (Medicare/Rochester Project) were 189/350 (0.540) for 1992 versus 959/1,003 (0.956) for the other years combined. Changes in Medicare data file transfer procedures may have produced the 1992 data shortfall. Medicare data should periodically be compared with source data to assess concordance.

Trends in the population-based incidence of squamous cell carcinoma of the skin first diagnosed between 1984 and 1992.

OBJECTIVE: To examine the incidence of first diagnosis of invasive squamous cell carcinoma (SCC) of the skin over time. DESIGN: Retrospective, population-based incidence study. SETTING: Enumerated, geographically isolated, semiurban population served by the Mayo Clinic and its affiliated hospitals and the Olmsted Medical Center, including its affiliated hospital in Rochester, Minn. METHODS: Using the Rochester Epidemiology Project databases that capture virtually all medical care provided to the residents of Rochester, we identified and reviewed records of all documented residents in whom histologically proven, invasive SCC of the skin was first diagnosed between 1984 and 1992. Age and sex stratum-specific rates were calculated, and age-adjusted rates observed over time for individuals aged 35 years or older were analyzed using Poisson regression. Adjusted rates were compared with the results of other studies. RESULTS: Review of 1630 records identified 511 incidence cases of SCC. Tumors located on the head and neck accounted for 66.4% of tumors in females and 72.9% in males. The annual age- and sex-specific incidence rates per 100,000 increased from 0 cases among males aged 0 to 14 years to 1286.0 cases among males aged 85 years or older. Over time, the annual age-adjusted incidence rates per 100,000 females rose from 46.5 (95% confidence interval [CI], 32.4-60.6) for the 1984 to 1986 period to 99.6 (95% CI, 80.4-118.7) for the 1990 to 1992 period and were 71.2 (95% CI, 61.7-80.8) overall. The corresponding rates for males were 125.9 (95% CI, 95.3-156.4), 191.0 (95% CI, 156.9-225.0), and 155.5 (95% CI, 137.0-174.0). The age- and sex-adjusted SCC incidence rates for the period from 1987 to 1989 and 1990 to 1992 exceeded those for the period from 1984 to 1986 (P = .03 and P < .001, respectively). Our age-adjusted rates for SCC were within the ranges seen in other white populations from temperate climates. CONCLUSION: The frequencies of first diagnosis of SCC are increasing at rates beyond those explainable by demographic shifts alone.

The incidence of primary angle-closure glaucoma in Olmsted County, Minnesota.

OBJECTIVES: To determine the incidence of primary angle-closure glaucoma (PACG) and to assess the visual outcomes of patients treated for PACG. DESIGN: Population-based retrospective incidence study. SETTING AND PATIENTS: Residents of Olmsted County, Minnesota, aged 40 years and older and diagnosed with PACG in the 13-year period between January 1, 1980, and December 31, 1992. MAIN OUTCOME MEASURE: Incident cases of PACG identified through the Medical Diagnostic Index of Mayo Clinic, Rochester, Minn, and the Rochester Epidemiology Project. RESULTS: Thirty-six incident cases were identified. The mean annual age-and sex-adjusted incidence per 100000 people aged 40 years and older was 8.3 (95% confidence interval, 5.6-11.0). The probability of monocular blindness associated with PACG at the time of diagnosis was 14%. Among patients not monocularly blind at diagnosis, the 5-year probability of developing monocular blindness associated with PACG was 4%. CONCLUSIONS: Primary angle-closure glaucoma is an uncommon disease in our community. Most of the patients blinded by PACG were blind at the time the condition was diagnosed.

Graft-related complications after abdominal aortic aneurysm repair: reassurance from a 36-year population-based experience.

PURPOSE: Graft-related complications must be factored into the long-term morbidity and mortality rates of abdominal aortic aneurysm (AAA) repair. However, the true incidence may be underestimated because some patients do not return to the original surgical center when a problem arises. METHODS: To minimize referral bias and loss to follow-up, we studied all patients who underwent AAA repair between 1957 and 1990 in a geographically defined community where all AAA operations were performed and followed by a single surgical practice. All patients who remained alive were asked to have their aortic grafts imaged. RESULTS: Among 307 patients who underwent AAA repair, 29 patients (9.4%) had a graft-related complication. At a mean follow-up of 5.8 years (range, < 30 days to 36 years), the most common complication was anastomotic pseudoaneurysm (3.0%), followed by graft thrombosis (2.0%), graft-enteric erosion/fistula (1.6%), graft infection (1.3%), anastomotic hemorrhage (1.3%), colon ischemia (0.7%), and atheroembolism (0.3%). Complications were recognized within 30 days after surgery in eight patients (2.6%) and at late follow-up in 21 patients (6.8%). These complications were observed at a median follow-up of 6.1 years for anastomotic pseudoaneurysm, 4.3 years for graft-enteric erosion, and 0.15 years for graft infection. Kaplan-Meier 5- and 10-year survival free estimates were 98% and 96% for anastomotic pseudoaneurysm, 98% and 95% for combined graft-enteric erosion/infection, and 98% and 97% for graft thrombosis. CONCLUSIONS: This 36-year population-based study confirms that the vast majority of patients who undergo standard surgical repair of an abdominal aortic aneurysm remain free of any significant graft-related complication during their remaining lifetime.

Incidence of nonarteritic anterior ischemic optic neuropathy.

PURPOSE: Nonarteritic anterior ischemic optic neuropathy is the most common acute optic nerve disease of adults over age 50 years. This study determined the incidence of acute nonarteritic anterior ischemic optic neuropathy in the circumscribed population of Olmsted County, Minnesota. METHODS: This was a retrospective study of the incidence of acute nonarteritic anterior ischemic optic neuropathy between 1981 and 1990. The Rochester Epidemiology Project medical records linkage system facilitates identification of the medical records of virtually all Olmsted County residents with a given diagnosis. All cases of acute nonarteritic anterior ischemic optic neuropathy that fulfilled certain inclusion and exclusion criteria were identified. RESULTS: Twenty-two cases in 21 patients (11 men and 10 women) were recorded. The crude annual incidence rate was 10.3 per 100,000 individuals (95% confidence interval [CI] = 5.1 to 18.4). When adjusted to the age and sex distribution of the 1990 United States white population, the incidence rate was 10.2 per 100,000 (95% CI = 6.5 to 15.6). At diagnosis, the median age was 72 years, mean visual acuity was 20/200 in the affected eye, and the most common visual field defect was an altitudinal deficit (10 cases). CONCLUSIONS: Although results of this small study should be interpreted cautiously, extrapolation of our findings to the United States white population indicates that nearly 5,700 new cases of acute nonarteritic anterior ischemic optic neuropathy may be expected to occur each year in this group.

Impact of arterial surgery and balloon angioplasty on amputation: a population-based study of 1155 procedures between 1973 and 1992.

BACKGROUND: Limited population-based data are available on trends in the incidence of arterial surgery, balloon angioplasty, and amputation for arterial occlusive disease of the legs over the past two decades. METHODS: We identified all elective and emergency arterial operations, balloon angioplasty procedures, and amputations performed for all residents of a defined community, Olmsted County, Minn., between 1973 and 1992. We focused on gender mix, type of procedure, and secular trends in utilization. RESULTS: A total of 1155 procedures were performed, including 733 arterial surgical procedures, 59 balloon angioplasty procedures, and 363 amputations (288 major and 75 minor). Emergency procedures were performed in 12%. Suprainguinal inflow procedures were the most common arterial reconstruction (60%) compared with infrainguinal procedures (40%). The incidence of all revascularization procedures increased in the first decade but reached a plateau after 1985. Utilization rates of revascularization procedures from 1988 to 1992 were higher for men (141.9/100,000 person-years [p-yr]) than women (57.4/100,000 p-yr.). Angioplasty (17.0/100,000 p-yr) rates lagged behind surgery until 1985, but tripled in the past 10 years and have not yet reached a plateau. Although minor amputation rates remain unchanged in 20 years, major amputation rates have been reduced by 50% from 36.7/100,000 p-yr between 1973 and 1977 to 19.0/100,000 p-yr from 1988 to 1992. CONCLUSIONS: From this long-term population-based analysis (1973 to 1992), we conclude that increased vascular surgery and balloon angioplasty rates have coincided with a significant reduction in major amputation rates in the past 10 years.

Perioperative respiratory complications in patients with asthma.

BACKGROUND: Patients with asthma are thought to be at high risk for pulmonary complications to develop during the perioperative period, and these complications may lead to serious morbidity. Existing medical records were reviewed to determine the frequency of and risk factors for perioperative pulmonary complications in a cohort of residents of Rochester, Minnesota, who had asthma and who underwent anesthesia and surgery at the Mayo Clinic in Rochester. METHODS: Medical records were reviewed for all residents of Rochester, Minnesota, who were initially diagnosed as having definite asthma according to strict criteria from 1 January 1964 through 31 December 1983 who subsequently had at least one surgical procedure involving a general anesthetic or central neuroaxis block at the Mayo Clinic (n = 706). RESULTS: Bronchospasm was documented in the perioperative records of 12 patients (1.7% [exact 95% confidence interval, 0.9 to 3%]). Postoperative respiratory failure developed in one of these patients. Laryngospasm developed in two additional patients during operation. All episodes of bronchospasm and laryngospasm in the immediate perioperative period were treated successfully. No episodes of pneumothorax, pneumonia, or death in the hospital were noted. For univariate analysis, characteristics associated with complications included the recent use of antiasthmatic drugs, recent asthma symptoms, and recent therapy in a medical facility for asthma. Patients in whom complications developed were significantly older at diagnosis and at surgery. CONCLUSIONS: The frequency of perioperative bronchospasm and laryngospasm was surprisingly low in this cohort of persons with asthma. These complications did not lead to severe respiratory outcomes in most patients. The frequency of complications was increased in older patients and in those with active asthma.

Cost-effectiveness analysis of interventions for congenital heart disease.

Expansion of the options available for the treatment of congenital heart disease has been accompanied by an increasing realization of the limits of our available health care resources. Cost-effectiveness analysis is one of several analytic approaches that can improve decisions about the appropriate use of technology in interventional pediatric cardiology and other fields. In this article, cost-effectiveness analysis is distinguished from related approaches, such as cost-benefit analysis. Then, basic principles of cost-effectiveness analysis are described. Next, the application of these principles is illustrated, using a recently published comparison of transcatheter versus surgical closure of patent ductus arteriosus. Finally, potential research implications of the surprising findings of this study are discussed.