Outcomes of adjunct posterior wall isolation in atrial fibrillation patients with cardiac implantable electronic devices.

BACKGROUND: Although pulmonary vein isolation (PVI) remains the cornerstone of catheter ablation of atrial fibrillation (AF), several studies have illustrated clinical benefits associated with PVI with posterior wall isolation (PWI). METHODS: This retrospective study investigated the outcomes of PVI alone versus PVI+PWI performed using the cryoballoon in patients with cardiac implantable electronic devices (CIEDs) and paroxysmal AF (PAF) or persistent AF (PersAF). RESULTS: Acute PVI was achieved in all patients using cryoballoon ablation. Compared to PVI alone, PVI+PWI was associated with longer cryoablation, fluoroscopy, and total procedure times. Adjunct radiofrequency was required to complete PWI in 29/77 patients (37.7%). Adverse events were similar with PVI alone versus PVI+PWI. But at 24 ± 7 months of follow-up, not only cryoballoon PVI+PWI was associated with improved freedom from recurrent AF (74.3% vs. 46.0%, P = .007) and all atrial tachyarrhythmias (71.4% vs. 38.1%, P = .001) in patients with PersAF, cryoballoon PVI+PWI also yielded greater freedom from AF (88.1% vs. 63.7%, P = .003) and all atrial tachyarrhythmias (83.3% vs. 60.8%, P = .008) in those with PAF. Additionally, PVI+PWI was associated with higher reductions in atrial tachyarrhythmia burden (97.9% vs. 91.6%, P < .001), need for cardioversion (5.2% vs. 23.6%, P < .001) and repeat catheter ablation (10.4% vs. 26.1%, P = .005), and a longer time-to-arrhythmia recurrence (16 ± 6 months vs. 8 ± 5 months, P < .001) in both PersAF and PAF patients. CONCLUSION: In CIED patients with PersAF or PAF, cryoballoon PVI+PWI is associated with a greater freedom from recurrent AF and atrial tachyarrhythmias, as compared to PVI alone during long-term follow-up.

Pulmonary Vein Isolation With and Without Posterior Wall Isolation in Paroxysmal Atrial Fibrillation: IMPPROVE-PAF Trial.

BACKGROUND: Prior studies have demonstrated clinical benefits associated with cryoballoon pulmonary vein isolation (PVI) and concomitant posterior wall isolation (PWI) in patients with persistent atrial fibrillation (AF). However, the role for this approach in patients with paroxysmal atrial fibrillation (PAF) remains unclear. OBJECTIVES: This study investigated the acute and long-term outcomes of PVI vs PVI+PWI using cryoballoon in patients with symptomatic PAF. METHODS: This retrospective study (NCT05296824) examined the outcomes of cryoballoon PVI (n = 1,342) vs cryoballoon PVI+PWI (n = 442) in patients with symptomatic PAF during long-term follow-up. Using the nearest-neighbor method, a 1:1 matched sample of patients receiving PVI alone and PVI+PWI was created. RESULTS: The matched cohort consisted of 320 patients (PVI: n = 160; PVI+PWI: n = 160). PVI+PWI was associated with longer cryoablation (23 ± 10 minutes vs 42 ± 11 minutes; P < 0.001) and procedure times (103 ± 24 minutes vs 127 ± 14 minutes; P < 0.001). In 39 (24.4%) of 160 patients, adjunct radiofrequency ablation was required for PVI+PWI. Adverse event rates were similar (PVI 3.8% vs PVI+PWI 1.9%; P = 0.31). Though there were no differences at 12 months, freedom from all atrial arrhythmias (67.5% vs 45.0%; P < 0.001) and AF (75.6% vs 55.0%; P < 0.001) were significantly greater with PVI+PWI vs PVI alone at 39 ± 9 months of follow-up. PVI+PWI was also associated with reduced long-term need for cardioversion (16.9% vs 27.5%; P = 0.02) and repeat catheter ablation (11.9% vs 26.3%; P = 0.001), and emerged as the only significant predictor of freedom from recurrent AF (HR: 2.79; 95% CI: 1.64-4.74; P < 0.001). CONCLUSIONS: Compared with cryoballoon PVI, cryoballoon PVI+PWI appears to be associated with greater freedom from recurrent atrial arrhythmias and AF in patients with PAF during long-term follow-up >3 years.

Enhancing the Visibility of Women in the ACS Division of Medicinal Chemistry (ACS MEDI).

On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).

Enhancing the Visibility of Women in the ACS Division of Medicinal Chemistry (ACS MEDI).

On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).

Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor.

KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.

Concomitant Pulmonary Vein and Posterior Wall Isolation Using Cryoballoon With Adjunct Radiofrequency in Persistent Atrial Fibrillation.

OBJECTIVES: The aim of this multicenter, randomized, single-blind study was to prospectively evaluate the short-and long-term outcomes of pulmonary vein isolation (PVI) versus PVI with concomitant left atrial posterior wall isolation (PWI) using the cryoballoon in patients with symptomatic persistent/long-standing persistent atrial fibrillation (P/LSP-AF). BACKGROUND: Some studies have suggested a clinical benefit associated with PVI+PWI in patients with P/LSP-AF. However, there are limited safety and efficacy data on this approach using cryoballoon ablation. METHODS: The immediate and long-term outcomes in patients with P/LSP-AF randomized to PVI (n = 55) versus PVI+PWI (n = 55) using the cryoballoon were prospectively examined. RESULTS: Baseline characteristics were similar. PVI was achieved in all patients (21 ± 11 min). PWI was attained using 23 ± 8 min of cryoablation. Adjunct radiofrequency ablation was required in 4 of 110 patients (7.3%) to complete PVI (3 ± 2 min) and in 25 of 55 patients (45.5%) to complete PWI (4 ± 6 min). Although left atrial dwell time (113 ± 31 min vs. 75 ± 32 min; p < 0.001) and total procedure time (168 ± 34 min vs. 127 ± 40 min; p < 0.001) were longer with PVI+PWI, this cohort required fewer intraprocedural cardioversions (89.1% vs. 96.4%; p = 0.04). Adverse events occurred in 5.5% in each group (p = 1.00). However, the incidence of recurrent atrial fibrillation at 12 months was significantly lower with PVI+PWI (25.5% vs. 45.5%; p = 0.028). Additionally, in a multivariate analysis, PVI+PWI emerged as a significant predictor of freedom from recurrent atrial fibrillation (odds ratio: 3.67; 95% confidence interval: 1.44 to 9.34; p = 0.006). CONCLUSIONS: In patients with P/LSP-AF, PVI+PWI using the cryoballoon is associated with a significant reduction in atrial fibrillation recurrence, but similar safety, as compared with PVI alone.

Left atrial posterior wall isolation in conjunction with pulmonary vein isolation using cryoballoon for treatment of persistent atrial fibrillation (PIVoTAL): study rationale and design.

BACKGROUND: There is growing evidence in support of pulmonary vein isolation (PVI) with concomitant posterior wall isolation (PWI) for the treatment of patients with symptomatic persistent atrial fibrillation (persAF). However, there is limited data on the safety and efficacy of this approach using the cryoballoon. OBJECTIVE: The aim of this multicenter, investigational device exemption trial (G190171) is to prospectively evaluate the acute and long-term outcomes of PVI versus PVI+PWI using the cryoballoon in patients with symptomatic persAF. METHODS: The PIVoTAL is a prospective, randomized controlled study ( ClinicalTrials.gov : NCT04505163) in which patients with symptomatic persAF refractory/intolerant to ≥ 1 class I-IV antiarrhythmic drug, undergoing first-time catheter ablation, will be randomized to PVI (n = 183) versus PVI+PWI (n = 183) using the cryoballoon in a 1:1 fashion. The design will be double-blind until randomization immediately after PVI, beyond which the design will transform into a single-blind. PVI using cryoballoon will be standardized using a pre-specified dosing algorithm. Other empiric ablations aside from documented arrhythmias/arrhythmias spontaneously induced during the procedure will not be permitted. The primary efficacy endpoint is defined as AF recurrence at 12 months, after a single procedure and a 90-day blanking period. Arrhythmia outcomes will be assessed by routine electrocardiograms and 7-14 day ambulatory electrocardiographic monitoring at 3, 6, and 12 months post-ablation. CONCLUSION: The PIVoTAL is a prospective, randomized controlled trial designed to evaluate the outcomes of PVI alone versus PVI+PWI using the cryoballoon, in patients with symptomatic persAF. We hypothesize that PVI+PWI will prove to be superior to PVI alone for prevention of AF recurrence.

Designing meditation for doctor well-being: can 'Om' help obstetrics and gynaecology doctors?

OBJECTIVE: The study aimed to measure the impact of meditation on participants' ability to regulate brain wave activity in high-stress situations, control physiological stress responses and improve subjective wellbeing. METHODS: Twelve obstetrics and gynaecology (O&G) doctors meditated for 20 minutes daily for 21 days utilising a portable EEG (electroencephalogram) providing instantaneous audio feedback. Their brain activity levels and salivary cortisol were measured before and after performing three surgical procedures. Participants were interviewed about their experiences and completed self-ratings of distress (e.g. DASS-21, Depression, Anxiety and Depression Scale). Data were analysed statistically and thematically. RESULTS: (a) Measures of pre- and post-operative brain activity showed no significantly higher levels of alpha waves. (b) Pre- and post-operative salivary cortisol levels did not significantly decrease. (c) DASS-21 scores showed significant decreases in levels of anxiety and stress. CONCLUSION: Results suggest that, with biofeedback meditation, O&G doctors can learn to reduce situational stress and improve mood overall through a focussed intervention.

VEGFR1 and VEGFR2 in Alzheimer's Disease.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-ß, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer's Post-Mortem Brain.

The neurological deterioration associated with Alzheimer's disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal.

Impact of irrigation flow rate and intrapericardial fluid on cooled-tip epicardial radiofrequency ablation.

BACKGROUND: The optimal irrigation flow rate (IFR) during epicardial radiofrequency (RF) ablation has not been established. OBJECTIVE: This study specifically examined the impact of IFR and intrapericardial fluid (IPF) accumulation during epicardial RF ablation. METHODS: Altogether, 452 ex vivo RF applications (10 g for 60 seconds) delivered to the epicardial surface of bovine myocardium using 3 open-irrigated ablation catheters (ThermoCool SmartTouch, ThermoCool SmartTouch-SF, and FlexAbility) and 50 in vivo RF applications delivered (ThermoCool SmartTouch-SF) in 4 healthy adult swine in the presence or absence of IPF were examined. Ex vivo, RF was delivered at low (≤3 mL/min), reduced (5-7 mL/min), and high (≥10 mL/min) IFRs using intermediate (25-35 W) and high (35-45 W) power. In vivo, applications were delivered (at 9.3 ± 2.2 g for 60 seconds at 39 W) using reduced (5 mL/min) and high (15 mL/min) IFRs. RESULTS: Ex vivo, surface lesion diameter inversely correlated with IFR, whereas maximum lesion diameter and depth did not differ. While steam pops occurred more frequently at low IFR using high power (ThermoCool SmartTouch and ThermoCool SmartTouch-SF), tissue disruption was rare and did not vary with IFR. In vivo, charring/steam pop was not detected. Although there were no discernible differences in lesion size with IFR, surface lesion diameter, maximum diameter, depth, and volume were all smaller in the presence of IPF at both IFRs. CONCLUSION: Cooled-tip epicardial RF ablation created using reduced IFRs (5-7 mL/min) yields lesion sizes similar to those created using high IFRs (≥10 mL/min) without an increase in steam pop/tissue disruption, whereas the presence of IPF significantly reduces the lesion size.

Organisational support for evidence-based practice: occupational therapists perceptions.

BACKGROUND: Barriers to the use of evidence-based practice extend beyond the individual clinician and often include organisational barriers. Adoption of systematic organisational support for evidence-based practice in health care is integral to its use. This study aimed to explore the perceptions of occupational therapy staff regarding the influence of organisational initiatives to support evidence-based practice on workplace culture and clinical practice. METHODS: This study used semi-structured interviews with 30 occupational therapists working in a major metropolitan hospital in Brisbane, Australia regarding their perceptions of organisational initiatives designed to support evidence-based practice. RESULTS: Four themes emerged from the data: (i) firmly embedding a culture valuing research and EBP, (ii) aligning professional identity with the Research and Evidence in Practice model, (iii) experiences of change: pride, confidence and pressure and (iv) making evidence-based changes to clinical practices. CONCLUSION: Organisational initiatives for evidence-based practice were perceived as influencing the culture of the workplace, therapists' sense of identity as clinicians, and as contributing to changes in clinical practice. It is therefore important to consider organisational factors when attempting to increase the use of evidence in practice.

"The biggest problem we've ever had to face": how families manage driving cessation with people with dementia.

BACKGROUND: It is recognized that people with dementia are likely to need to stop driving at some point following diagnosis. Driving cessation can lead to negative outcomes for people with dementia and their family caregivers (FC), who often experience family conflict and tension throughout the process. Family experiences surrounding driving cessation have begun to be explored but warrant further examination. METHODS: Using a descriptive phenomenological approach, semi-structured interviews were undertaken with key stakeholders, including 5 retired drivers with dementia, 12 FC, and 15 health professionals (HP). Data were analyzed inductively to explore the needs and experiences of people with dementia and FC. RESULTS: The data revealed a range of possible interactions between people with dementia and FC. These were organized into a continuum of family dynamics according to levels of collaboration and conflict: in it together, behind the scenes, active negotiations, and at odds. At the in it together end of the continuum, people with dementia and FC demonstrated collaborative approaches and minimal conflict in managing driving cessation. At the at odds end, they experienced open conflict and significant tension in their interactions. Contextual factors influencing family dynamics were identified, along with the need for individualized approaches to support. CONCLUSIONS: The continuum of family dynamics experienced during driving cessation may help clinicians better understand and respond to complex family needs. Interventions should be tailored to families' distinctive needs with consideration of their unique contextual factors influencing dynamics, to provide sensitive and responsive support for families managing driving cessation.

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF).

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer's disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3ß (GSK3ß) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.

Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization.

BACKGROUND: Surgical exclusion of the left atrial appendage (LAA) can frequently yield incomplete closure. OBJECTIVE: We evaluated the ischemic stroke/systemic embolization (SSE) risk in patients with atrial fibrillation (AF) and complete LAA closure (cLAA) vs incompletely surgically ligated LAA (ISLL) and LAA stump after surgical suture ligation. METHODS: Seventy-two patients (CHA2DS2-VASc score 4.1 ± 1.9) underwent surgical LAA ligation in conjunction with mitral valve/AF surgery and postoperative LAA evaluation using computerized tomographic angiography. RESULTS: Overall, cLAA was detected in 46 of 72 patients (64%), ISLL in 17 patients (24%), and LAA stump in 9 patients (12%). The incidences of oral anticoagulation (OAC) and recurrent AF were similar among the 3 groups during 44 ± 19 months of follow-up. SSE occurred in 2% of patients with cLAA vs 24% with ISLL and 0% with LAA stump (P = .006). None of the patients with SSE were receiving OAC, and all had recurrent AF during follow-up. Additionally, patients with SSE exhibited a significantly smaller ISLL neck diameter (2.8 ± 1.0 vs 7.1 ± 2.1 mm; P = .002). The annualized SSE risk was 1.9% (entire cohort), 6.5% (ISLL patients), 14.4% (ISLL patients not receiving OAC), and 19.0% (ISLL neck diameter ≤5.0 mm) per 100 patient-years of follow-up. The latter risk was nearly 5 times greater than predicted by conventional risk-stratification schemes. Moreover, ISLL emerged as an independent predictor of SSE in univariate analyses and as the sole predictor of SSE in a multivariate analysis. CONCLUSION: In patients with AF, ISLL is a predictor of SSE, independent of conventional risk stratification schemes. Consequently, OAC should be strongly considered in this high-risk cohort.

The role of brain-derived neurotrophic factor (BDNF) in the development of neurogenic detrusor overactivity (NDO).

Neurogenic detrusor overactivity (NDO) is a well known consequence of spinal cord injury (SCI), recognizable after spinal shock, during which the bladder is areflexic. NDO emergence and maintenance depend on profound plastic changes of the spinal neuronal pathways regulating bladder function. It is well known that neurotrophins (NTs) are major regulators of such changes. NGF is the best-studied NT in the bladder and its role in NDO has already been established. Another very abundant neurotrophin is BDNF. Despite being shown that, acting at the spinal cord level, BDNF is a key mediator of bladder dysfunction and pain during cystitis, it is presently unclear if it is also important for NDO. This study aimed to clarify this issue. Results obtained pinpoint BDNF as an important regulator of NDO appearance and maintenance. Spinal BDNF expression increased in a time-dependent manner together with NDO emergence. In chronic SCI rats, BDNF sequestration improved bladder function, indicating that, at later stages, BDNF contributes NDO maintenance. During spinal shock, BDNF sequestration resulted in early development of bladder hyperactivity, accompanied by increased axonal growth of calcitonin gene-related peptide-labeled fibers in the dorsal horn. Chronic BDNF administration inhibited the emergence of NDO, together with reduction of axonal growth, suggesting that BDNF may have a crucial role in bladder function after SCI via inhibition of neuronal sprouting. These findings highlight the role of BDNF in NDO and may provide a significant contribution to create more efficient therapies to manage SCI patients.

Unmet health and rehabilitation needs of people with long-term neurological conditions in Queensland, Australia.

The survival and life expectancy rates of people with traumatic and degenerative neurological conditions are increasing, sometimes up to several decades. Yet compared to the general population, people with a disability continue to experience poorer health and are at greater risk of developing secondary health problems and facing barriers to services they require. These trends have significant implications for provision of health and rehabilitation services. In this study, the adequacy of health and rehabilitation services provided to people with long-term neurological conditions and their unmet needs were explored from the perspectives of individual users, their nominated family members and key service providers. A qualitative research design with maximum variation sampling was used. Data were collected from semi-structured interviews with 65 participants comprising 25 long-term care service users, nominated family members or friends (n = 22) and care service providers (n = 18) in Queensland, Australia. All service users needed assistance with usual daily activities, and 22 were wheelchair dependent. The hours of funded personal care ranged from 2 to 201 hours per week. Data were analysed using framework analysis. Participants generally perceived that specialist medical and hospital services were adequate and satisfactory. They valued supportive health and rehabilitation professionals and receiving client-centred physical rehabilitation. However, the majority of participants (n = 17) had perceived unmet needs for physical rehabilitation (n = 14), other health or rehabilitation services (n = 10) or counselling (n = 6). Community-based physical maintenance rehabilitation was often perceived as inadequate, costly or inconveniently located. Participants highlighted the importance of personal and family counselling and information provision at time points such as diagnosis. The findings contribute to the limited international evidence on the gaps in health and rehabilitation services for people with neurological conditions receiving lifetime care services in the community. A continuum of integrated rehabilitation services to minimise avoidable impairments, optimise independence and functioning, and sustain quality of life is warranted.

Design and nuclear magnetic resonance (NMR) structure determination of the second extracellular immunoglobulin tyrosine kinase A (TrkAIg2) domain construct for binding site elucidation in drug discovery.

The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain triggers intracellular signaling cascades. In the periphery, this promotes the pain phenotype and, in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein-ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a ß-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF ( 1WWW .pdb), and the (1)H-(15)N correlation spectra confirm that both NGF and a competing small molecule interact at the known binding interface in solution.

The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer's disease.

This review, gathered from diverse sources, shows how our microbiome influences health and ultimately how well we age. Evidence linking oral bacteria to Alzheimer's disease (AD) is discussed in the context of aging, drawing together data from epidemiological, experimental, genetic, and environmental studies. Immunosenescence results in increased bacterial load as cell-mediated and humoral immune responses wane. The innate immune system gradually takes over; contributing to the rise in circulating proinflammatory cytokines such as TNFα. Maintaining the integrity of the blood-brain barrier (BBB) against a backdrop of increasing bacterial load is important. Aging may favor the proliferation of anaerobes in the mouth eliciting a robust TNFα response from the oral epithelium. Prolonged exposure to high levels of circulating TNFα compromises the integrity of the BBB. Sensitive techniques now detect the "asymptomatic" presence of bacteria in areas previously thought to be sterile, providing new insights into the wider distribution of components of the microbiome. These "immune-tolerated" bacteria may slowly multiply elsewhere until they elicit a chronic inflammatory response; some are now considered causal in instances of atherosclerosis and back pain. Inflammatory processes have long been associated with AD. We propose for a subset of AD patients, aging favors the overgrowth of oral anaerobes established earlier in life provoking a pro-inflammatory innate response that weakens the BBB allowing bacteria to spread and quietly influence the pathogenesis of AD. Finally, we suggest that human polymorphisms considered alongside components of the microbiome may provide new avenues of research for the prevention and treatment of disease.