Memory decline in older individuals predicts an objective indicator of oral health: findings from the Sydney Memory and Ageing Study.

BACKGROUND: Growing evidence suggests that there is an association between poor oral health and cognitive function in late adulthood. However, most studies to date have relied on cross-sectional research methods that do not permit inferences about the temporality of any association. Moreover, the few longitudinal studies that do exist have typically relied on small samples and quite limited cognitive or oral health assessments. The aim of the present study was therefore designed to provide the first direct evaluation of whether cognitive function is predictive of poor oral health in older adults. METHODS: This longitudinal research included data from 339 participants aged 70 years or older from The Sydney Memory and Ageing Study (MAS), a large cohort of healthy community-dwelling older adults. Cognitive function was assessed using a battery of tests at baseline (Wave 1) in 2005 and six years later (Wave 4) in 2011. In 2015 (Wave 6), participants were assessed for oral health using the Oral Health Assessment Tool (OHAT), number of functional occluding pairs of natural teeth and sublingual resting saliva pH (SRSpH). Ordinal least squares regression analysis was used to model the effect of cognitive function on total OHAT score, and binomial logistic regression used for SRSpH and occluding pairs of functional teeth. RESULTS: Two models were tested. In the partially adjusted model, age, gender and years of education were included. The fully adjusted model additionally included medical conditions, general health, depression, smoking, alcohol consumption, functionality, and dental care utilization. The key finding to emerge was that a six-year change in memory (from Wave 1 to Wave 4) was associated with lower sublingual resting saliva pH at Wave 6 in partially (Odds Ratio (OR) = 0.65) and fully adjusted model (OR = 0.63). CONCLUSIONS: This longitudinal study provides further evidence that a relationship between cognitive function and oral health exists, and also points to this relationship potentially being bi-directional, as previous evidence suggests. The findings from the study also suggest that older adults who present with greater than normal memory decline at an earlier point in life were more likely to experience poor oral health when this was evaluated at a later time-point, four years later.

Can chronic oral inflammation and masticatory dysfunction contribute to cognitive impairment?

PURPOSE OF REVIEW: This article provides an overview of current literature focused on oral health and cognitive impairment in older adulthood, focusing in particular on whether oral inflammation, tooth loss and masticatory dysfunction might increase the risk of cognitive impairment in this age group. RECENT FINDINGS: There is now general acceptance that cognitive impairment contributes to poor oral health, largely through detrimental changes in behaviours related to maintaining good oral hygiene. There is more limited evidence for the reverse causal direction, but at least some studies now suggest that inflammatory mechanisms, tooth loss and masticatory dysfunction each have the potential to contribute to cognitive decline. SUMMARY: Poorer oral health significantly correlates with cognitive dysfunction, and at least some studies suggest that there may be a bi-directional causal relationship. Randomized controlled trials assessing cognitive abilities in relation to oral hygiene or oral health interventions, or provision of removable or fixed (implant-supported) dentures, are encouraged.

Single injection of a novel nerve growth factor coacervate improves structural and functional regeneration after sciatic nerve injury in adult rats.

The prototypical neurotrophin, nerve growth factor (NGF), plays an important role in the development and maintenance of many neurons in both the central and peripheral nervous systems, and can promote functional recovery after peripheral nerve injury in adulthood. However, repair of peripheral nerve defects is hampered by the short half-life of NGF in vivo, and treatment with either NGF alone or NGF contained in synthetic nerve conduits is inferior to the use of nerve autografts, the current gold standard. We tested the reparative ability of a single local injection of a polyvalent coacervate containing polycation-poly(ethylene argininylaspartate diglyceride; PEAD), heparin, and NGF, in adult rats following sciatic nerve crush injury, using molecular, histological and behavioral approaches. In vitro assays demonstrated that NGF was loaded into the coacervate at nearly 100% efficiency, and was protected from proteolytic degradation. In vivo, the coacervate enhanced NGF bioavailability, leading to a notable improvement in motor function (track walking analysis) after 30days. The NGF coacervate treatment was also associated with better weight gain and reduction in atrophy of the gastrocnemius muscle. Furthermore, light and electron microscopy showed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in NGF coacervate-treated rats compared with control groups. Expression of markers of neural tissue regeneration (MAP-2, S-100ß, MBP and GAP-43), as well as proliferating Schwann cells and myelin-axon relationships (GFAP and NF200), were also increased. These observations suggest that even a single administration of NGF coacervate could have therapeutic value for peripheral nerve regeneration and functional recovery.

Neurotrophic actions initiated by proNGF in adult sensory neurons may require peri-somatic glia to drive local cleavage to NGF.

The nerve growth factor (NGF) precursor, proNGF, is implicated in various neuropathological states. ProNGF signals apoptosis by forming a complex with the receptors p75 and sortilin, however, it can also induce neurite growth, proposed to be mediated by the receptor of mature NGF, tyrosine kinase receptor A (TrkA). The way in which these dual effects occur in adult neurons is unclear. We investigated the neurotrophic effects of proNGF on peptidergic sensory neurons isolated from adult mouse dorsal root ganglia and found that proNGF stimulated neurite extension and branching, requiring p75, sortilin and TrkA. Neurite growth rarely occurred in sortilin-expressing neurons but was commonly observed in TrkA-positive, sortilin-negative neurons that associated closely with sortilin-positive glia. ProNGF was unable to induce local trophic effects at growth cones where sortilin-positive glia was absent. We propose that in adult sensory neurons the neurotrophic response to proNGF is mediated by NGF and TrkA, and that peri-somatic glia may participate in sortilin- and p-75 dependent cleavage of proNGF. The potential ability of local glial cells to provide a targeted supply of NGF may provide an important way to promote trophic (rather than apoptotic) outcomes under conditions where regeneration or sprouting is required.

Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice.

INTRODUCTION: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated. AIM: To assess whether treatment with a novel PARP-1 inhibitor, GPI 15427, could improve neurovascular dysfunction in corpus cavernosum (CC) from diabetic mice. METHODS: Diabetes was induced by streptozotocin in male MF1 mice; duration was 6 weeks. Intervention GPI 15427 treatment (20mg/kg/day intraperitoneal [i.p.]) was given for 2 weeks following 4 weeks of untreated diabetes. CC strips were mounted in aerated organ baths for measurement of pharmacological or electrical stimulation-evoked changes in smooth muscle tension. MAIN OUTCOME MEASURES: Contractile responses to noradrenergic stimulation and to pharmacological agents stimulating endothelium-dependent and -independent relaxation, and nerve-mediated relaxations against a background precontraction. RESULTS: Contractions in response to phenylephrine or activation of noradrenergic nerves were not significantly altered by diabetes. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted CC was approximately 28% reduced by diabetes: GPI 15427 treatment completely corrected this diabetic deficit. Similarly, maximal nitric oxide (NO)-mediated endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, against phenylephrine precontraction, were attenuated approximately 37% and 23% by diabetes, respectively. These deficits were completely reversed by PARP-1 inhibition. Furthermore, GPI 15427 corrected a modest diabetic deficit in sensitivity to nitroprusside (EC(50) reduced by 0.14 log units); a similar trend was observed for acetylcholine-induced relaxation. CONCLUSIONS: GPI 15427 treatment provides marked benefits for NO-dependent neurovascular function in diabetic mouse CC. Therefore, PARP-1 inhibition may be worthy of further investigation for diabetes-associated ED.

Impaired cavernous reinnervation after penile nerve injury in rats with features of the metabolic syndrome.

INTRODUCTION: The metabolic syndrome is a cluster of cardiovascular risk factors that predispose toward the development of diseases such as diabetes. Erectile dysfunction (ED) is common in men with metabolic syndrome, but its etiology is poorly understood. Pro-erectile nitrergic nerves innervating penile erectile tissue are also susceptible to mechanical injury during pelvic surgical procedures, which can lead to sexual dysfunction. AIMS: The aims of this article are: (i) to examine erectile function in an experimental model of metabolic syndrome, the phosphoenolpyruvate carboxykinase (PEPCK)-overexpressing rat; and (ii) to study function and cavernous reinnervation after penile nerve crush injury, which permits regeneration, in transgenic rats. METHODS: We analyzed the density of noradrenergic and nitrergic nerves and performed organ bath pharmacology to assess neurogenic activity. MAIN OUTCOME MEASURES: By analyzing changes in neural structure, function, and pharmacologic responses of cavernous tissue after nerve crush injury, we were able to reveal neurologic deficits in rats with metabolic syndrome. RESULTS: Animals with features of metabolic syndrome did not develop notable changes in cavernous autonomic nerve density or nerve-evoked smooth muscle activity. However, regeneration of nitrergic nerves after crush injury in transgenic rats was impaired compared with injured controls. This was manifested as a deficit in axon regrowth and responses to axon activation. However, unlike injured controls, injured PEPCK-overexpressing rats did not develop a reduced maximal response to the nitric oxide (NO) donor, sodium nitroprusside. This suggests preserved NO responsiveness in tissues from rats with metabolic syndrome, despite impaired regeneration and return of function. CONCLUSIONS: This study revealed that rats with features of metabolic syndrome display impaired cavernous nerve regeneration after penile nerve injury, but the degree of functional impairment may be attenuated due to reduced plasticity of NO signaling. This reinnervation deficit may be of clinical relevance for understanding why ED persists in some (particularly aged) men after pelvic surgery.

Deafferentation and axotomy each cause neurturin-independent upregulation of c-Jun in rodent pelvic ganglia.

The pelvic ganglia provide autonomic innervation to pelvic viscera and urogenital organs. These neurons are susceptible to axonal injury during pelvic surgical procedures, yet their regenerative mechanisms are poorly understood. The AP-1 transcription factor component, c-Jun, has been strongly linked to regenerative events in injured sensory, sympathetic and somatic motor neurons and is considered to be required for regeneration. Our aims were: (1) to identify whether c-Jun was upregulated by injury in pelvic parasympathetic neurons, and (2) whether injury was required for c-Jun upregulation, by performing deafferentation (i.e., severance of lumbar and sacral spinal inputs), which elicits sprouting of axon collaterals from pelvic ganglion neurons but does not injure them. A week after penile nerve axotomy in rats and mice, upregulation of c-Jun occurred in numerous glia within pelvic ganglia and almost half of the retrogradely-labelled penis-projecting neurons but also occurred in many uninjured noradrenergic neurons. We also identified upregulation of c-Jun in many pelvic ganglion neurons and glia a week after deafferentation, suggesting that c-Jun expression is activated in sprouting but uninjured neurons. A c-Jun response was retained in injured or deafferented parasympathetic neurons in neurturin knockout mice. In summary, neurturin-independent c-Jun expression within pelvic ganglion neurons does not require a direct injury and may instead be causally linked to axonal sprouting, regardless of stimulus. This study revealed mechanisms involved in structural remodelling of pelvic autonomic nerve circuits that may be modulated to improve regenerative processes.

Loss of nitrergic neurotransmission to mouse corpus cavernosum in the absence of neurturin is accompanied by increased response to acetylcholine.

The neurotrophic factor, neurturin (NTN), plays an important role in parasympathetic neural development. In the penis, parasympathetic nitrergic/cholinergic nerves mediate the erectile response. However, despite reduced parasympathetic penile innervation in mice lacking the NTN receptor, glial cell line-derived neurotrophic factor family receptor alpha (GFRalpha)2, they are capable of erection and reproduction. Our aim was to assess neural regulation of erectile tissues from mice lacking NTN. Responses of cavernosal smooth muscle were studied in vitro, monitoring agonist- and nerve-evoked changes in tension. Frequency-dependent nerve-evoked relaxations in the presence of guanethidine were markedly reduced in the mutant mice compared to wild types (19 vs 72% of phenylephrine pre-contraction). Atropine reduced the amplitude in wild-type mice to 61%, but abolished relaxations in knockout mice. In wild-type and knockout animals, nitric oxide synthase inhibition abolished neurogenic relaxations. In NTN knockout animals, EC(50) values for nitric oxide-dependent relaxations to acetylcholine and muscarine were increased approximately 0.5 log units. In contrast, contractions to electrical stimulation or phenylephrine, and relaxations to bradykinin or the nitric oxide donor, sodium nitroprusside, were unaltered. Immunohistochemistry confirmed that nerves immunoreactive for nitric oxide synthase, vesicular acetylcholine transporter and vasoactive intestinal polypeptide were substantially reduced in cavernosum of NTN knockout mice. Parallel immunohistochemical and pharmacological studies in GFRalpha2 knockout animals showed the same changes from their wild types as the NTN knockout animals. The data demonstrate that NTN is essential for normal development of penile erection-inducing nerves and that its absence leads to increased responsiveness to muscarinic agonists, possibly as a compensatory mechanism.