Antipsychotic Medication Risk of Dementia and Death: A Propensity Matched Cohort Study.

OBJECTIVE: This study aimed to compare the incidence of dementia and all-cause mortality up to 20 years post-treatment in an index non-demented cohort between antipsychotic (AP) medication treatment and non-AP treatment groups. METHODS: All patients in Kaiser Permanente Northern California with a major psychiatric diagnosis between 01/01/1996 and 12/31/2000, age ≥ 50 years, and without dementia diagnosis were included. The study cohort was divided into a "user group", patients treated with AP for ≥ 365 days (n = 1,829), and a "non-user group", propensity score-matched on age, sex, and race (n = 9,145). The association between AP exposure and dementia or mortality during the follow-up period (01/01/2001-12/31/2015) was evaluated using Cox proportional hazard models adjusted for psychiatric diagnosis, comorbidities, and other medications. RESULTS: The user group had a hazard ratio (HR) of 2.2 (CI 1.8-2.7) for dementia and 1.3 (CI 1.2- 1.5) for death. The onset of dementia in the user group was significantly higher in patients aged ≤ 65 years (p < 0.001). The user group was sub-grouped into atypical, typical, and both; HR for dementia was 1.7 (CI 1.2-2.4), 2.5 (CI 1.9-3.1), and 1.8 (CI 1.4-2.4), respectively. Dementia and mortality were significantly higher in patients concurrently treated with benzodiazepine (HR 1.3; CI 1.2-1.5 and HR 1.4; CI 1.3-1.5) or tricyclic antidepressants (HR 1.2; CI 1.1-1.4 and HR 1.1; CI 1.0-1.2), respectively. CONCLUSION: Our preliminary results reveal an association between AP treatment and increased rates of both dementia and mortality. Future research is needed to substantiate our current findings.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Molecular stress response in the CNS of mice after systemic exposure to interferon-alpha, ionizing radiation and ketamine.

We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adult mice 30min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4h after systemic exposure to interferon-alpha (IFN-alpha) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-alpha (a single i.p. injection at 1 x 10(5)IU/kg) or whole body gamma-radiation (10cGy or 2Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-alpha, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-alpha treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex and hippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

The expression of Troponin T1 gene is induced by ketamine in adult mouse brain.

The glutamatergic system has been implicated in neuropsychiatric disorders, such as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have paradoxical effects of neuroprotection and neurotoxicity. We investigated gene expression in brain tissue of adult mice treated with ketamine to characterize the expression profiles and to identify the affected metabolic pathways. Adult male mice were treated by a single intraperitoneal (i.p.) injection of either s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were differentially expressed in ketamine-treated mouse brains compared with control mice using oligonucleotide microarray analysis, and the expression of Troponin T1 (Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced Tnnt1 expression was confirmed and characterized using RNA in situ hybridization techniques in paraffin embedded brain tissue sections. Tnnt1 expression was induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to interact directly with FoxO1, which is involved in multiple peripheral metabolic pathways and central energy homeostasis. Our findings suggest that the induction of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the genes involved in the metabolic syndromes observed in neuropsychiatric disorders.

A father of four consecutive trisomic pregnancies with elevated frequencies of associated aneuploid sperm.

A couple with normal somatic karyotypes had four consecutive trisomic pregnancies, each involving a different chromosome, of which two children were liveborn with confirmed paternal-origin trisomies. The apparently healthy father produced abnormally high frequencies of disomic sperm for each of the four chromosomes involved in the trisomic pregnancies (P< 0.003, by sperm fluorescence in situ hybridization (FISH)). His elevated sperm aneuploidies persisted over a 2-year period and affected all chromosomes evaluated, suggesting that he had a genome-wide defect in meiotic disjunction. He also had the highest frequencies of aneuploid sperm reported for any healthy man to date. His frequencies of aneuploid sperm were comparable to the peak frequencies of the transient responses reported in some cancer patients after receiving aneugenic chemotherapies. These findings indicate that apparently healthy men can produce abnormally high frequencies of sperm aneuploidies that suggest that this condition may contribute to recurrent trisomic pregnancies.

NOVP chemotherapy for Hodgkin's disease transiently induces sperm aneuploidies associated with the major clinical aneuploidy syndromes involving chromosomes X, Y, 18, and 21.

The objective of this research was to determine whether Novantrone, Oncovin, Velban, and Prednisone (NOVP) combination chemotherapy for Hodgkin's disease increases the frequencies of the specific types of aneuploid sperm that might elevate the risk of fathering a child with one of the major clinical aneuploidy syndromes, i.e., Down (disomy 21 sperm), Edward (disomy 18 sperm), Turner (nullisomy sex sperm), XYY (disomy Y sperm), triple X (disomy X sperm), or Klinefelter (XY sperm). A four-chromosome multicolor sperm fluorescence in-situ hybridization assay that simultaneously evaluates chromosomes 18, 21, X, and Y was applied to semen provided by four healthy men and to repeated samples of eight Hodgkin's disease patients before treatment, 35-50 days after treatment to examine the effects of treatment on male meiotic cells, and 1-2 years after treatment to measure the persistence of damage. There were chromosome-specific variations in baseline frequencies and significant inductions of all of the detectable types of sperm aneuploidies: XY sperm (14-fold increase), disomy 18 (7-fold), nullisomy sex (3-fold), disomy 21 (3-fold), and disomy X and Y (approximately 2-fold each). Disomy 21 was about twice as frequent as disomy 18, and neither showed a preferential segregation with a sex chromosome. Extrapolating across the genome, approximately 18% of sperm carried a numerical abnormality after NOVP treatment of meiotic cells. Induced effects did not persist to 1-2 years after treatment, suggesting that persistent spermatogonial stem cells were not sensitive to NOVP. These findings establish the hypothesis that conception shortly after certain chemotherapies can transiently increase the risks of fathering aneuploid pregnancies that terminate during development or result in the birth of children with major human aneuploidy syndromes.