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Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4b Y358C ) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the App NL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14 C-2-deoxyglucose autoradiography, thioflavin-S staining of β-amyloid (Aβ) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, App NL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in App NL-G-F /Pde4b Y358C mice, without a decrease in Aβ plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in App NL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in App NL-G-F /Pde4b Y358C versus App NL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old App NL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the App NL-G-F model and a promising therapeutic target for AD., (© 2024. The Author(s).)

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2-5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABA A receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation is a common feature of many age-related conditions including neurodegenerative diseases such as Alzheimer's disease. Cellular senescence is a state of irreversible cell-cycle arrest, thought to contribute to neurodegenerative diseases partially via induction of a chronic pro-inflammatory phenotype. In this study, we used a mouse model of genetically enhanced NF-κB activity (nfκb1 -/- ), characterized by low-grade chronic inflammation and premature aging, to investigate the impact of inflammaging on cognitive decline. We found that during aging, nfkb1 -/- mice show an early onset of memory loss, combined with enhanced neuroinflammation and increased frequency of senescent cells in the hippocampus and cerebellum. Electrophysiological measurements in the hippocampus of nfkb1 -/- mice in vitro revealed deficits in gamma frequency oscillations, which could explain the decline in memory capacity. Importantly, treatment with the nonsteroidal anti-inflammatory drug (NASID) ibuprofen reduced neuroinflammation and senescent cell burden resulting in significant improvements in cognitive function and gamma frequency oscillations. These data support the hypothesis that chronic inflammation is a causal factor in the cognitive decline observed during aging., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P). We found an age-dependent reduction in the power of the gamma (20-80 Hz) frequency oscillations in slices taken from mice aged 9-16 months (9+A30P), that was not present in either young 2-6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of α-syn. These findings provide mechanistic insights into the consequences of over-expression of α-syn which might contribute to cognitive decline., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

The purpose of this investigation was to describe the pharmacokinetics of sublingual triazolam in children. Nine healthy children (64-98 months old) received 0.25 or 0.375 mg of sublingual triazolam before dental treatment. Plasma triazolam concentrations were measured by gas chromatography/mass spectrometry and analyzed by noncompartmental methods. The peak concentration was 4.9 +/- 2.0 ng/mL (mean +/- SD), time to peak was 75 +/- 32 minutes, the elimination half-life was 91 +/- 32 minutes, and apparent clearance was 17.6 +/- 8.8 mL x kg(-1) x min(-1). Children were tested for gait ataxia, amnesia, and diplopia during a screening session and again after triazolam. Ninety minutes after drug administration, seven of nine children demonstrated ataxia, and three of nine demonstrated amnesia. Peak triazolam concentrations were similar in children with or without ataxia, but they were significantly higher in children with amnesia compared with those without amnesia. Six children demonstrated diplopia 30 and 120 minutes after triazolam; however, peak triazolam concentrations were similar in both groups. Sublingual administration was an acceptable alternative route of triazolam delivery in children.

A dual radioisotopic method was employed to study the rate of gastric emptying of meals in ten males with an average age of 31 years and 10 elderly males with an average age of 76.4 years. All study subjects were fed a standardized 900-g meal labeled with a liquid (111indium-DTPA) and solid (99mtechnetium-tagged liver) phase isotopic marker. There were no significant differences in solid food emptying rates between the young and aged men. A delay in liquid emptying, however, was observed in the aged men. The clinical significance of this observation is unknown.

A previously healthy 29-year-old man developed multiple hepatic abscesses secondary to Fusobacterium nucleatum. No underlying local disease was found. The leading portal of entry for the bacterium may have been the oral cavity; 4 days before the onset of his illness he had had extensive dental work. Immunological evaluation during the illness and in late convalescence (16 weeks after onset) revealed a persistent B cell abnormality characterized by markedly depressed in vitro secretion of immunoglobulins in response to pokeweed mitogen; however, serum immunoglobulins and IgG subclasses were normal. Abnormal numbers of suppressor T cells (OKT8+) and increased suppressor function were also present. Anaerobic pyogenic liver abscesses may occur in the absence of obvious underlying disease, but this case suggests that there may be an association with in vitro abnormalities of the immune system.

Pentoxifylline, a hemorrheologic agent that lowers whole blood viscosity by increasing red cell membrane deformability, recently was approved by the Food and Drug Administration for the treatment of intermittent claudication. The effect of this drug on the phenotypic expression of red cell blood group antigens was studied with cells collected from six patients with intermittent claudication. After in vivo treatment with pentoxifylline, the serologic expression of the Wrb antigen increased. Comparative studies, using hemagglutination titration techniques, with red cells collected before treatment and 1 month after treatment, showed an increase in titer of at least two tubes and an increase in score of greater than 10 in all six patient samples drawn after treatment. No in vivo serologic changes were observed in any of the other antigens studied (A, B, D, C, E, c, e, M, N, S, s, U, P1, Leb, K, k, Fya, Fyb, Jka, Jkb, Yta). Protein analysis (sodium-dodecylsulfate polyacrylamide gel electrophoresis, silver stain) of red cell membranes prepared from blood collected before treatment and 1 month after treatment showed an increase in band density in the 24,000 and 14,000 dalton regions in the samples drawn after treatment. In vitro treatment of red cells with pentoxifylline and one of its major metabolites did not affect the phenotypic expression of any of the antigens studied, including Wrb.