Association of periodontitis with cognitive decline and its progression: Contribution of blood-based biomarkers of Alzheimer's disease to this relationship.

AIM: To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood-based markers of Alzheimer's disease. MATERIALS AND METHODS: Data from a 2-year follow-up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full-mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini-Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aß)1-40 , Aß1-42 , phosphorylated and total Tau (p-Tau and t-Tau) were determined at baseline, 12 and 24 months. RESULTS: Periodontitis was associated with poor cognitive performance (MMSE: ß = -1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0-3.1). Subjects with periodontitis showed greater baseline levels of p-Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p < .001) and Aß1-40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p = .036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p = .005). CONCLUSIONS: Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p-Tau and Aß1-40 may play a role in this association.

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer's disease spectrum.

PURPOSE: Recent evidence suggests that PET imaging with amyloid-ß (Aß) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aß PET, contributes to AD progression remains unexplored. METHODS: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aß-positive cognitively impaired, and 207 Aß-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. RESULTS: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aß, and WMH burden. Most of these associations were also observed in Aß-negative cognitively impaired individuals. CONCLUSION: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer's Disease and Other Neurodegenerative Diseases.

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

Periodontitis and systemic markers of neurodegeneration: A case-control study.

AIM: To investigate whether periodontitis is associated with amyloid beta (Aß) peptides and whether systemic inflammation could act as a potential mediator of this link. MATERIALS AND METHODS: A case-control study was designed including 75 patients with periodontitis (cases) and 75 age-balanced and gender-matched participants without periodontitis (controls). Full-mouth periodontal evaluation was performed in all participants. Demographic, clinical and behaviour data were also recorded. Fasting blood samples were collected, and serum levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), Aß1-40 and Aß1-42 were determined. RESULTS: Cases showed higher levels of IL-6 (8.7 ± 3.2 vs. 4.8 ± 0.5 pg/ml), hs-CRP (3.3 ± 1.2 vs. 0.9 ± 0.7 mg/L), Aß1-40 (37.3 ± 6.0 vs. 30.3 ± 1.8 pg/ml) and Aß1-42 (54.5 ± 10.6 vs. 36.5 ± 10.0 pg/ml) when compared to controls (all p < .001). Diagnosis of periodontitis was statistically significantly associated with circulating Aß1-40 ( ßcoefficientadjusted  = 6.9, 95% CI: 5.4-8.3; p < .001) and Aß1-42 ( ßcoefficientadjusted  = 17.8, 95% CI: 14.4-21.3; p < .001). Mediation analysis confirmed hs-CRP and IL-6 as mediators of this association. CONCLUSIONS: Periodontitis is associated with increased peripheral levels of Aß. This finding could be explained by enhanced systemic inflammation that can be seen in patients with periodontitis.

Is Periodontal Disease Associated with Alzheimer's Disease? A Systematic Review with Meta-Analysis.

BACKGROUND: In the last decade, several observational studies have suggested that there exists an association between periodontal disease (PD) and Alzheimer's disease (AD). The aim of this systematic review was to investigate whether or not this link exists. SUMMARY: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline for systematic review was used and registered at PROSPERO (CRD42016035377). The search strategy included using electronic databases and by hand searching articles published up to January 2016. MEDLINE via PubMed, EMBASE and Web of Science were searched by 2 independent reviewers. Observational studies including patients meeting criteria for both AD and PD were eligible to be included in the analysis. Quality assessment of selected studies was performed by the Newcastle-Ottawa Scale. From a total of 550 titles and abstracts, 5 studies were included (2 cross-sectional, 2 case-control and one cohort study) in the review. A fixed effects meta-analysis showed that the presence of PD is associated with the presence of AD (OR 1.69, 95% CI 1.21-2.35). When only severe forms of PD were evaluated, a significant association was also observed (OR 2.98, 95% CI 1.58-5.62). Key Messages: In the present review, a significant association was observed between PD and AD. Further studies should be carried out in order to investigate the direction of the association and factors that may confound it.

Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.

The Role of Inflammatory Diet and Vitamin D on the Link between Periodontitis and Cognitive Function: A Mediation Analysis in Older Adults.

Patients suffering from periodontitis are at a higher risk of developing cognitive dysfunction. However, the mediation effect of an inflammatory diet and serum vitamin D levels in this link is unclear. In total, 2062 participants aged 60 years or older with complete periodontal diagnosis and cognitive tests from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014 were enrolled. The Consortium to Establish a Registry for Alzheimer's disease (CERAD) word learning subtest (WLT) and CERAD delayed recall test (DRT), the animal fluency test (AFT) and the digit symbol substitution test (DSST) was used. Dietary inflammatory index (DII) was computed via nutrition datasets. Mediation analysis tested the effects of DII and vitamin D levels in the association of mean probing depth (PD) and attachment loss (AL) in all four cognitive tests. Periodontitis patients obtained worse cognitive test scores than periodontally healthy individuals. DII was negatively associated with CERAD-WLT, CERAD-DRT, AFT and DSST, and was estimated to mediate between 9.2% and 36.4% of the total association between periodontitis with cognitive dysfunction (p < 0.05). Vitamin D showed a weak association between CERAD-DRT, AFT and DSST and was estimated to between 8.1% and 73.2% of the association between periodontitis and cognitive dysfunction (p < 0.05). The association between periodontitis and impaired cognitive function seems to be mediated both by a proinflammatory dietary load and vitamin D deficiency. Future studies should further explore these mediators in the periodontitis-cognitive decline link.

Staging the cognitive continuum in prodromal Alzheimer's disease with episodic memory.

It is unclear whether episodic memory is an appropriate descriptor of the cognitive continuum in mild cognitive impairment (MCI). Here, we investigated the ability of episodic memory to track cognitive changes in patients with MCI with biomarker evidence of Alzheimer's disease (AD). We examined 387 MCI amyloid-positive subjects, cognitively staged as "early" or "late" on the basis of episodic memory impairment. Cross-sectional and longitudinal comparisons between these 2 groups were performed for each amyloid, tau, and neurodegeneration (AT(N)) profile. Cross-sectional analyses indicate that "early" MCI represents a transitional phase between normal cognition and "late" MCI in the AD biomarker pathway. After adjusting by confounders and levels of A, T, and (N), "late" MCI progressed significantly faster than "early" MCI only in profiles with both abnormal amyloid and tau markers (A+T+(N)- p < 0.05, A+T+(N)+ p < 0.001). Episodic memory staging is useful for describing symptoms in prodromal AD and complements the AT(N) profiles. Our findings might have implications for the Numeric Clinical staging scheme of the National Institute on Aging and Alzheimer's Association research framework.

Prediction of Alzheimer's disease dementia with MRI beyond the short-term: Implications for the design of predictive models.

Magnetic resonance imaging (MRI) volumetric measures have become a standard tool for the detection of incipient Alzheimer's Disease (AD) dementia in mild cognitive impairment (MCI). Focused on providing an earlier and more accurate diagnosis, sophisticated MRI machine learning algorithms have been developed over the recent years, most of them learning their non-disease patterns from MCI that remained stable over 2-3 years. In this work, we analyzed whether these stable MCI over short-term periods are actually appropriate training examples of non-disease patterns. To this aim, we compared the diagnosis of MCI patients at 2 and 5 years of follow-up and investigated its impact on the predictive performance of baseline volumetric MRI measures primarily involved in AD, i.e., hippocampal and entorhinal cortex volumes. Predictive power was evaluated in terms of the area under the ROC curve (AUC), sensitivity, and specificity in a trial sample of 248 MCI patients followed-up over 5 years. We further compared the sensitivity in those MCI that converted before 2 years and those that converted after 2 years. Our results indicate that 23% of the stable MCI at 2 years progressed in the next three years and that MRI volumetric measures are good predictors of conversion to AD dementia even at the mid-term, showing a better specificity and AUC as follow-up time increases. The combination of hippocampus and entorhinal cortex yielded an AUC that was significantly higher for the 5-year follow-up (AUC = 73% at 2 years vs. AUC = 84% at 5 years), as well as for specificity (56% vs. 71%). Sensitivity showed a non-significant slight decrease (81% vs. 78%). Remarkably, the performance of this model was comparable to machine learning models at the same follow-up times. MRI correctly identified most of the patients that converted after 2 years (with sensitivity >60%), and these patients showed a similar degree of abnormalities to those that converted before 2 years. This implies that most of the MCI patients that remained stable over short periods and subsequently progressed to AD dementia had evident atrophies at baseline. Therefore, machine learning models that use these patients to learn non-disease patterns are including an important fraction of patients with evident pathological changes related to the disease, something that might result in reduced performance and lack of biological interpretability.