Worldwide, approximately 50 million people have dementia among which 50–60% are diagnosed with Alzheimer’s disease (AD) (World Health Organization). It is estimated these numbers will almost double by 2030 and triple by 2050. Delaying the onset of AD by only 2 years could reduce the number of AD cases in 50 years by 2 million. These predictions underscore the importance of identifying modifiable risk factors earlier in life.
Recent animal and epidemiological studies suggested that peripheral inflammation and dysbiotic conditions contributed to AD pathogenesis [
1‐
5]. Periodontal disease (PerioD) is a peripheral inflammatory, dysbiotic condition affecting more than 10% and 50% of the young and older population, respectively [
6]. It results from the interaction between the dysbiotic bacteria and the host immune response leading to structural damage to tissues surrounding affected teeth [
7].
Epidemiological data of various designs also linked PerioD and AD and reported that measures of PerioD were associated with cognitive dysfunction, cognitive decline, dementia, and AD, with odds and hazard risk ratios in the mild to moderate range [
8‐
10]. Our studies showed increased brain amyloid accumulation [
11], and cognitive dysfunction [
12] in elderly with measures of periodontal disease. Most studies, including ours, investigated these relationships in elderly. Only a few studies included young populations [
9,
13], and therefore, it is unclear whether these relationships are also found in youth. Studying younger populations is significant for several reasons: AD pathology starts early in life [
14] with a long preclinical phase; longer periodontal exposure increases the AD risk [
15]; the young population are most likely to lack other comorbidities that would affect AD, and preventive measures could be implemented early. Periodontal disease can occur in the young population in the form of chronic periodontitis or aggressive periodontitis. Aggressive periodontal disease is especially destructive and has significant local and systemic inflammation [
16,
17]. By definition, aggressive periodontitis is found in young systemically healthy people, and its prevalence could be higher in some populations [
18]. Therefore, this population would be ideal to investigate the role of periodontal disease in AD [
15]. Episodic memory is one of the first memory domains to be impaired in AD and can be detected years before AD diagnosis [
19,
20]. In addition, episodic memory associated with AD pathology in preclinical and prodromal stages [
21,
22]. We hypothesized that young subjects with periodontal disease would have impaired episodic memory compared to controls. We also hypothesized that salivary proinflammatory molecules IL-1β and TNF-α would inversely correlate with delayed memory.
Methods and materials
This was a monocenter, cross-sectional comparative study of 3 clinical groups of young medically healthy subjects from the western region of Romania. The subjects were derived from a pool of 149 subjects that participated in a previous retrospective study [
18]. These subjects presented to the Prosthodontics Department of the Faculty of Dental Medicine, Victor Babeş University of Medicine and Pharmacy, Timisoara, for comprehensive dental treatment. This study was approved by the University Ethics Committee. Informed consent was reviewed and signed by all subjects (No27/2017). Sixty subjects were asked to participate in the “cognitive study.” Among them, 40 subjects agreed and were recruited: 10 with aggressive periodontitis (AGG_P), 20 with chronic mild-moderate periodontitis (CR_P), and 10 with no signs of periodontitis (NL_P). In addition to fulfilling the inclusion and exclusion criteria described below, subjects were required to agree to a neuropsychological evaluation and saliva collection. Diagnosis of periodontal conditions was done by two calibrated periodontists both with more than 20 years of clinical and research experience using panoramic radiographs as we previously published [
18]. Radiographic images were also used to assess caries, tooth number, endodontic treatments, and periapical pathology [
18].
Results
Table
1 shows subject characteristics. All subjects were systemically healthy, and mean age was 34 (SD=5). Subjects were overall well educated, only 14% were smokers, and gender was equally distributed. When we compared the periodontal groups, there were no differences in age, gender, smoking, BP, dental lesions, or depression scores. We found differences in tooth number among the groups (
p=0.01) and the percentage of subjects with only high school education (
p=0.01).
Table 1
Characteristics of the study population
Demographics |
Age [mean (SD)] | 33.67(5.34) | 31.10 (5.38) | 34.45 (5.06) | 34.70 (5.52) | 0.21 | 0.11 | 0.13 | 0.90 |
Gender (n (%)) | 0.95 | 0.80 | 1.00 | 0.80 |
Male | 21 (51%) | 5 (50%) | 11 (55%) | 5 (50%) | | | | |
Female | 19 (48%) | 5 (50%) | 9 (45%) | 5 (50%) | | | | |
Education level (n (%)) | | | | | 0.01 | 0.44 | 0.01 | 0.01 |
High school | 9 (22.5%) | 0 (0%) | 2 (10%) | 7 (70%) | | | | |
Trade education | 8 (20%) | 2 (20% | 6 (30%) | 0 (0%) | | | | |
University education | 23 (57.5%) | 8 (80%) | 12 (60%) | 3 (30%) | | | | |
Dental characteristics (mean (SD)) |
Num teeth | 25.85 (4.19) | 28.20 (2.15) | 26.55 (3.59) | 22.10 (4.63) | 0.01 | 0.22 | 0.01 | 0.02 |
Implants | 0.23 (0.73) | 0.10 (0.32) | 0.40 (1.00) | 0.00 (0.00) | 0.28 | 0.65 | 0.74 | 0.40 |
Root number | 0.48 (1.28) | 0.50 (1.58) | 0.10 (0.31) | 1.20 (1.87) | 0.10 | 0.98 | 0.32 | 0.16 |
Carious lesions | 3.55 (2.85) | 3.00 (2.49) | 3.05 (2.19) | 5.10 (3.90) | 0.35 | 0.78 | 0.25 | 0.20 |
Crowns | 3.00 (4.88) | 1.90 (4.04) | 3.65 (4.99) | 2.80 (5.67) | 0.41 | 0.25 | 0.91 | 0.42 |
Root canal | 2.33 (2.28) | 1.40 (1.58) | 3.15 (2.58) | 1.60 (1.71) | 0.08 | 0.07 | 0.91 | 0.09 |
Fillings | 6.23 (3.81) | 5.50 (3.60) | 7.60 (3.87) | 4.20 (2.97) | 0.07 | 0.23 | 0.48 | 0.02 |
Periapical lesions | 0.70 (1.16) | 0.20 (0.63) | 0.75 (0.79) | 1.10 (1.91) | 0.13 | 0.07 | 0.20 | 0.85 |
Smoking (n (%)) | | | | | 0.90 | 0.78 | 0.64 | 0.79 |
Yes | 14 (35%) | 3 (30%) | 7 (35%) | 4 (40%) | | | | |
No | 26 (65%) | 7 (70%) | 13 (65%) | 6 (60%) | | | | |
Blood pressure (n (%)) | | | | | 0.14 | 0.56 | 0.07 | 0.11 |
Normal | 26 (65%) | 8 (80%) | 14 (70%) | 4 (40%) | | | | |
Elevated | 14 (35%) | 2 (20%) | 6 (30%) | 6 (60%) | | | | |
HRSD17 (mean (SD)) | 3.30 (1.91) | 2.80 (2.30) | 3.40 (1.60) | 3.60 (2.22) | 0.52 | 0.31 | 0.39 | 0.85 |
Discussion
Our study showed for the first time that among young systemically healthy subjects, those with AGG_P had impaired delayed episodic memory and learning rate compared to NL_P and CR_P. This conclusion was based on RAVLT and other cognitive tests showing significantly lower scores in AGG_P compared to NL_P. RAVLT delayed recall, percent forgetting, and Prague test were also lower in CR_P compared to NL_P. These results appear to be independent of age or education as both were not significant in any model. These results showed that periodontal disease may constitute a risk for cognitive impairment and this risk was most elevated in AGG_P. In addition, we found a significant positive correlation of salivary IL-1β and immediate recall scores suggesting a role in cognition.
Episodic memory is thought to be the first memory domain to be impaired in AD [
32]. Studies showed that in addition to delayed recall, learning curves were also impaired in those with MCI compared to those with normal cognition [
33]. These tests discriminated the most between cognitively normal and AD [
34] and were predictors of early AD [
33,
35]. Impairments in these cognitive tests have been associated with brain neurodegeneration and the lesions of AD. Immediate recall also depends on the learning ability and information coding, and these impairments have been associated with atrophy in frontal as well as temporal lobe [
32], while delayed recall task was associated with the medial temporal area. Early memory impairment was found to associate with early AD with pathological findings localized in the mesial temporal lobes, especially in the hippocampal formation and entorhinal cortices [
36,
37]. In addition to memory, attention assessed by Prague test was also compromised in both CR and AGG_P groups, and these results were consistent with our previous studies in elderly [
12].
Our findings raised the possibility that in young subjects with periodontal disease, memory dysfunction is present, signs of brain abnormalities may exist, and increased risk of AD later in life is possible.
The difference in cognitive tests between NL_P and those with AGG_P was consistent across multiple cognitive tests. These results are not surprising as AGG_P is highly destructive and associates with more severe immune responses compared to CR_P. The microbial load is also higher and characterized by many pathogenic bacteria. The difference between those with CR_P and NL_P was not as consistent. This is likely due to less severe periodontal disease, less aggressive immune response, or less microbial burden. An additional reason could be the limited sample size. The cognitive tests for CR_P were slightly lower than those of NL_P, and therefore, a larger number could result in significance.
Proinflammatory cytokines such as IL
-1β and TNF-α could contribute to neuroinflammation. However, they also have physiological roles [
38]. IL
-1β is required for proper learning and therefore immediate memory [
39]. In our young population, higher IL-1β correlated with higher immediate memory. Their effects can also depend on timing, concentration, and duration of exposure [
40]. We speculate that higher IL-1β facilitates cognition. On the other hand, we do not know the source of salivary IL
-1β. It can be derived from the oral cavity or can be derived from systemic sources. Systemic sources are unlikely as these subjects are young and systemically healthy. It can also be derived from the brain. To untangle the role of oral cytokines in cognition and brain pathology, longitudinal studies are warranted with serial exams, and levels of IL-1β in saliva, blood, and CSF.
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