A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease.

INTRODUCTION: We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. METHODS: Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. RESULTS: Gamma flicker was safe, tolerable, and adherable. Participants' neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. DISCUSSION: These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

Menopause occurs late in life in the captive chimpanzee (Pan troglodytes).

Menopause in women occurs at mid-life. Chimpanzees, in contrast, continue to display cycles of menstrual bleeding and genital swelling, suggestive of ovulation, until near their maximum life span of about 60 years. Because ovulation was not confirmed hormonally, however, the age at which chimpanzees experience menopause has remained uncertain. In the present study, we provide hormonal data from urine samples collected from 30 female chimpanzees, of which 9 were old (>30 years), including 2 above the age of 50 years. Eight old chimpanzees showed clear endocrine evidence of ovulation, as well as cycles of genital swelling that correlated closely with measured endocrine changes. Endocrine evidence thus confirms prior observations (cyclic anogenital swelling) that menopause is a late-life event in the chimpanzee. We also unexpectedly discovered an idiopathic anovulation in some young and middle-aged chimpanzees; this merits further study. Because our results on old chimpanzees validate the use of anogenital swelling as a surrogate index of ovulation, we were able to combine data on swelling and urinary hormones to provide the first estimates of age-specific rates of menopause in chimpanzees. We conclude that menopause occurs near 50 years of age in chimpanzees as it does in women. Our finding identifies a basic difference between the human and chimpanzee aging processes: female chimpanzees can remain reproductively viable for a greater proportion of their life span than women. Thus, while menopause marks the end of the chimpanzee's life span, women may thrive for decades more.

Ovarian aging in squirrel monkeys (Saimiri sciureus).

In female squirrel monkeys (Saimiri sciureus), the reproductive period normally extends from approximately 2.5 years to the mid-teens. In the present study, we examined the age-associated cytological changes in the ovaries of 24 squirrel monkeys ranging in age from newborn to approximately 20 years. We found a significant, age-related decline in the number of primordial follicles, with the most pronounced loss occurring between birth and 5 years. After approximately 8 years of age, relatively few primordial follicles were evident in the ovarian sections examined. An unusual feature of the aging squirrel monkey ovary is the emergence of highly differentiated, encapsulated clusters of granulosa cells that increase in size and number, particularly after the age of 8 years. Many of these cells express anti-Müllerian hormone, and, histologically, the clusters resemble granulosa cell tumors in humans. However, granulosa cell clusters (GCCs) are present in both ovaries of all older squirrel monkeys, and they display no obvious signs of malignancy, suggesting that they are a normal feature of ovarian aging in this species. Our findings indicate that reproductive senescence in female squirrel monkeys, as in other primates, involves the inexorable depletion of ovarian follicles. In addition, the consistent appearance of abundant, well-differentiated clusters of granulosa cells in older squirrel monkeys, prior to the cessation of reproduction, suggests that these structures may influence the later stages of reproductive potential in this species. Analysis of GCCs in older squirrel monkeys also could yield insights into the pathophysiology of granulosa cell tumors in humans.

Menopause in nonhuman primates?

A gradual alteration in the mechanisms underlying reproduction and fertility characterizes the aging process in human females. These changes culminate in menopause, conventionally defined as a cessation of menstrual cycles that marks the end of reproductive capacity. In fact, a central and defining event in menopause is the discontinuation of ovulation, which is correlated with a number of structural and functional changes in the reproductive axis. Despite several decades of research, a degree of uncertainty remains as to whether nonhuman primates undergo menopause, and whether they are suitable models of human reproductive senescence. We review some of the controversies that have clouded our understanding of reproductive aging in nonhuman primates, including issues of definition, timing, comparability of data from wild versus captive populations, and cross-species comparisons. The existing data support the view that menopause occurs in a number of primate species and is not unique to humans.

Menopause in female rhesus monkeys.

Fifteen female rhesus monkeys (Macaca mulatto), ranging in age from 8 to 34 years, were studied for one year to characterize the endocrine and menstrual changes associated with menopause in this species. Five monkeys were premenopausal; these younger monkeys, ages 8-11 years, menstruated and showed cyclic ovarian activity during the 12-month study period, as evidenced by menses and periodic elevations of serum estradiol (E2) and luteinizing hormone (LH) concentrations. Four females, ages 24-26 years, were in transition to menopause. Two of these perimenopausal females menstruated and secreted E2 and LH in a periodic fashion; the other two females showed elevated LH concentrations, consistently low E2 levels, and no evidence of menstruation. Six females, ages 27-34 years, were clearly postmenopausal; LH concentrations were high, whereas E2 concentrations were uniformly low. There was a significant inverse correlation between basal E2 concentrations and age, and a significant positive correlation between age and LH concentrations across all 15 animals. Hormonal changes indicative of ovulation, when they occurred, were generally restricted to the winter and early spring months. Histological analysis of ovaries from four postmenopausal females revealed little or no evidence of active folliculogenesis. These data indicate that menopause in female rhesus monkeys does not occur until the second half of thethird decade of life. © 1995 Wiley-Liss, Inc.

Effects of anesthetic agents on the adrenocortical system of female baboons.

Invasive surgical procedures are often used to study the reproductive and adrenocortical endocrine systems in primates. Anesthetic agents must, therefore, be used that have the least confounding effects on these systems. The present study was designed to characterize various adrenocortical endocrine responses of female baboons (Papio anubis), each treated for 120 minutes with an infusion of ketamine HCl (6 mg/min) in 5% dextrose in water (0.40 ml/min), a combination of ketamine and acetylpromazine (0.6 mg acetylpromazine and 6 mg ketamine HCl/min) in 5% dextrose in water, or inhalation of vaporized halothane (1.0% halothane, N2O 25%, 1 liter/min; O2 75%, 3 liters/min). Blood samples were collected throughout the treatment period, and serum was assayed for prolactin (PRL), dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and cortisol (F). No significant elevations in DHA, F, or PRL concentrations were found following infusion of ketamine alone. Only serum DHAS concentrations were significantly altered after long-term exposure to ketamine. Acetylpromazine increased PRL concentrations tenfold to levels significantly greater than those in ketamine- and halothane-treated animals but had no effect on serum DHA, DHAS, or F. Treatment with halothane had no effect on serum PRL, DHA, or DHAS but did suppress F (>40%) concentrations over time. These data indicate that ketamine is best suited for the collection of biological samples when deep analgesia is not required but that halothane is preferable in the latter situation.

Effects of age, lactation, and repeated cycles on rhesus monkey copulatory intervals.

Young, sexually mature female rhesus monkeys copulate on more days prior to conception than do older females, and this prolonged discrete mating period is associated with an earlier rise in serum estradiol prior to the first ovulation of the breeding season. The influence of repeated ovulatory cycles and the presence of a suckling infant on the copulatory patterns were examined in two separate analyses. Extending previous work, young, nulliparous females copulated on more days at the first ovulation of the breeding season than did older, multiparous females. However, the duration of the copulatory period at the second ovulation of the breeding season was similar and significantly shorter for both age groups. Furthermore, the presence of a suckling infant did not influence the duration of the mating periods in adult, multiparous females. The onset of copulatory behavior for all females was associated with serum estradiol concentrations of approximately 90 pg/ml, indicating that the age and cycle differences in the duration of the copulatory periods are due to the time course of serum estradiol prior to ovulation. A separate, longitudinal analysis of the duration of the mating period associated with the first ovulation of three successive breeding seasons indicated that females copulated on more days during their first ovulatory cycle of their first breeding season. These data indicate that the copulatory interval is longer for females during the first ovulation of the breeding season, and this pattern is accentuated in young, sexually mature animals.

Prenatal ionizing irradiaton and early postnatal growth of Colombian and Bolivian squirrel monkeys (Saimiri sciureus).

Fetal squirrel monkeys of Bolivian and Colombian origin were exposed to 100 rad cobalt-60 radiation in utero and carried to term by the dams. Body weight, head circumference, crown-rump length, and food intake were measured during the first 28 postnatal days. Significant subspecies differences were noted in both mothers and offspring, the Colombian squirrel monkeys being generally larger than the Bolivians. The irradiated offspring weighed significantly less, had significantly smaller crania, and consumed significantly less food than control animals. A statistically nonsignificant decrement was also evident in the crown-rump length of radiation-treated infants.