Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer’s disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer’s disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer’s disease.

BACKGROUND-The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS-We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS-After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P = 0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P = 0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P = 0.15) or clomiphene alone (8 of 85, 9%; P = 0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P = 0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS-In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.

An enigmatic feature of age-related neurodegenerative diseases is that they seldom, if ever, are fully manifested in nonhuman species under natural conditions. The neurodegenerative tauopathies are typified by the intracellular aggregation of hyperphosphorylated, microtubule-associated protein tau (MAPT) and the dysfunction and death of affected neurons. We document the first case of tauopathy with paired helical filaments in an aged chimpanzee (Pan troglodytes). Pathologic forms of tau in neuronal somata, neuropil threads, and plaque-like clusters of neurites were histologically identified throughout the neocortex and, to a lesser degree, in allocortical and subcortical structures. Ultrastructurally, the neurofibrillary tangles consisted of tau-immunoreactive paired helical filaments with a diameter and helical periodicity indistinguishable from those seen in Alzheimer’s disease. A moderate degree of Aβ deposition was present in the cerebral vasculature and, less frequently, in senile plaques. Sequencing of the exons and associated introns in the genomic MAPT locus disclosed no mutations that are associated with the known human hereditary tauopathies, nor any polymorphisms of obvious functional significance. Although the lesion profile in this chimpanzee differed somewhat from that of Alzheimer’s disease, the co-presence of paired helical filaments and Aβ-amyloidosis indicates that the molecular mechanisms for the pathogenesis of the two canonical Alzheimer lesions - neurofibrillary tangles and senile plaques - are present in aged chimpanzees.

Aged nonhuman primates accumulate large amounts of human-sequence amyloid β (Aβ) in the brain, yet they do not manifest the full phenotype of Alzheimer's disease (AD). To assess the biophysical properties of Aβ that might govern its pathogenic potential in humans and nonhuman primates, we incubated the benzothiazole imaging agent Pittsburgh compound B (PIB) with cortical tissue homogenates from normal aged humans, humans with AD, and from aged squirrel monkeys, rhesus monkeys, and chimpanzees with cerebral Aβ-amyloidosis. Relative to humans with AD, high-affinity PIB binding is markedly reduced in cortical extracts from aged nonhuman primates containing levels of insoluble Aβ similar to those in AD. The high-affinity binding of PIB may be selective for a pathologic, human-specific conformation of multimeric Aβ, and thus could be a useful experimental tool for clarifying the unique predisposition of humans to Alzheimer's disease. INDEXING TERMS

Radiolabeled Pittsburgh compound B (PIB) is a benzothiazole imaging agent that usually binds with high affinity, specificity, and stoichiometry to cerebral β-amyloid (Aβ) in patients with Alzheimer's disease. Among a cohort of ten AD subjects examined postmortem, we describe a case of idiopathic, end-stage Alzheimer's disease with heavy Aβ deposition yet substantially diminished high-affinity binding of 3 H-PIB to cortical homogenates and unfixed cryosections. Cortical tissue samples were analyzed by immunohistochemistry, electron microscopy, ELISA, immunoblotting, MALDI-TOF mass spectrometry, in vitro 3 H-PIB binding and 3 H-PIB autoradiography. The PIB-refractory subject met the histopathological criteria for AD. However, cortical tissue from this case contained more vascular β-amyloidosis, higher levels of insoluble Aβ40 and Aβ42, and a higher ratio of Aβ40:Aβ42 than did tissue from the nine comparison AD cases. Furthermore, cerebral Aβ from the PIB-refractory subject displayed an unusual distribution of low-and high-molecular weight Aβ oligomers, as well as a distinct pattern of N-and Cterminally truncated Aβ peptides in both the soluble and insoluble cortical extracts. Genetically, the patient was apolipoprotein-Eε4 heterozygous, and exhibited no known AD-associated mutations in the genes of the β-amyloid precursor protein, presenilin-1 or presenilin-2. Our findings suggest that PIB may differentially recognize polymorphic forms of multimeric Aβ in humans with Alzheimer's disease. In addition, while the prevalence of PIB-refractory cases in the general AD population remains to be determined, the paucity of high-affinity binding sites in this AD case cautions that minimal PIB retention in positron-emission tomography scans of demented patients may not always rule out the presence of Alzheimer-type Aβ pathology.

BACKGROUND The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P = 0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P = 0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P = 0.15) or clomiphene alone (8 of 85, 9%; P = 0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P = 0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.)

Deposition of the Aβ peptide in senile plaques and cerebral Aβ angiopathy can be stimulated in Aβ-precursor protein-transgenic mice by the intracerebral injection of dilute brain extracts containing aggregated Aβ seeds. Growing evidence implicates a prion-like mechanism of corruptive protein templating in this phenomenon, in which aggregated Aβ itself is the seed. Unlike prion disease, which can be induced de novo in animals that are unlikely to spontaneously develop the disease, previous experiments with Aβ seeding have employed animal models that, as they age, eventually will generate Aβ lesions in the absence of seeding. In the present study, we first established that a transgenic rat model expressing human Aβ-precursor protein (APP21 line) does not manifest endogenous deposits of Aβ within the course of its median lifespan (30 months). Next, we injected 3-month-old APP21 rats intrahippocampally with dilute Alzheimer brain extracts containing aggregated Aβ. After a 9-month incubation period, these rats had developed senile plaques and cerebral Aβ angiopathy in the injected hippocampus, whereas control rats remained free of such lesions. These findings underscore the co-dependence of agent and host in governing seeded protein aggregation, and show that cerebral Aβ-amyloidosis can be induced even in animals that are relatively refractory to the spontaneous origination of parenchymal and vascular deposits of Aβ.

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