Dietary Components and Nutritional Strategies for Dementia Prevention in the Elderly.

BACKGROUND: For decades, evidence from observational studies and randomized controlled trials has converged to suggest associations of dietary components, foods, and dietary patterns with dementia. With population aging and a projected exponential expansion of people living with dementia, formulating nutritional strategies for dementia prevention has become a research hotspot. OBJECTIVE: This review aimed to summarize available data on the roles of specific dietary components, food groups, and dietary patterns in dementia prevention among the elderly. METHODS: Database search was carried out using PubMed, the Cochrane Library, EMBASE, and Medline. RESULTS: Polyphenols, folate, vitamin D, omega-3 fatty acids, and ß-carotene might decrease the risk of dementia. Consumption of green leafy vegetables, green tea, fish, and fruits is recommended. However, saturated fat, a diet rich in both dietary copper and saturated fat, aluminum from drinking water, and heavy drinking might increase dementia risk. Healthy dietary patterns, especially the Mediterranean diet, were proven to bring more cognitive benefits than single dietary components. CONCLUSION: We discussed and summarized the evidence on the roles of dietary components and patterns in dementia prevention among the elderly and found that some factors were closely associated with dementia risk in elderly. This may pave the way for the identification of dietary components and patterns as new therapeutic targets for dementia prevention in the elderly population.

Associations of White Matter Hyperintensities with Cognitive Decline: A Longitudinal Study.

White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer's disease (AD) dementia compared with controls (p < 0.001) and mild cognitive impairment (p = 0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p = 0.029; p = 0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p < 0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ɛ4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD.

Common Variant in TREM1 Influencing Brain Amyloid Deposition in Mild Cognitive Impairment and Alzheimer's Disease.

Triggering receptor expressed on myeloid cells-1 (TREM1) has been reported to associate with Alzheimer's disease (AD) pathology. Recently, TREM1 variant rs2234246A was reported to regulate TREM-1 protein and mRNA levels. We explored the effect of rs2234246 on AD specific biomarker (amyloid-ß PET) to look into the role of this TREM1 locus in AD pathogenesis. We calculated the association of the TREM1 locus with amyloid deposition at baseline and follow-up using both multiple linear models and mixed effect models respectively in 522 the Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. We also analyzed the association of TREM1 with this marker in subregions during the AD process. In the pooled sample, TREM1 rs2234246A was associated with the levels of mean standard uptake volume ratios (SUVRs) at baseline (p = 0.02) and the length of follow-up (p = 0.04) in the cross-sectional analysis and longitudinal study. Subgroup analyses showed no correlation between rs2234246A and amyloid deposition in the cognitively normal (CN) group. In the mild cognitive impairment (MCI) group, TREM1 rs2234246A reached significance at baseline (p = 0.04) and the length of follow-up (p = 0.04). In the AD group, TREM1 rs2234246A was associated with mean SUVR at baseline (p < 0.001) and the length of follow-up (p = 0.001). In subregion analyses, TREM1 rs2234246A was detected to be related to Aß deposition. This study demonstrated an association between TREM1 variant rs2234246 and brain amyloidosis. Our findings implied that this variant is involved in AD by influencing Aß neuropathology.

Modifiable risk factors for cognitive impairment in Parkinson's disease: A systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Cognitive impairment is a common and devastating manifestation in Parkinson's disease (PD). We aimed to identify modifiable risk factors for PD with cognitive impairment. METHODS: We systematically searched PubMed and the Cochrane Library from June 1937 to September 2018 and included prospective cohort studies with random-effects model used to combine estimates. Primary analyses for all types of cognitive impairments and subgroup analyses for separate outcomes were conducted. RESULTS: A total of 31,298 articles were identified, of which 32 articles with 18 factors met the inclusion criteria for meta-analysis. In the primary analysis, 9 modifiable risk factors were found to increase the risk of PD with cognitive impairment, including postural-instability-gait disorder (relative risk = 3.76, 95% confidence interval = 1.36-10.40), hallucinations (relative risk = 3.09, 95% confidence interval = 1.61-5.93), orthostatic hypotension (relative risk = 2.98, 95% confidence interval = 1.41-6.28), cerebrovascular disease (relative risk = 1.52, 95% confidence interval = 1.01-2.28), diabetes mellitus (relative risk = 1.47, 95% confidence interval = 1.13-1.92), obesity (relative risk = 1.38, 95% confidence interval = 1.15-1.65), cardiac disease (relative risk = 1.35, 95% confidence interval = 1.17-1.56), alcohol consumption (relative risk = 1.32, 95% confidence interval = 1.15-1.52), and smoking (relative risk = 1.31, 95% confidence interval = 1.14-1.50). In the subgroup analysis, postural-instability-gait disorder subtype, orthostatic hypotension and hallucinations may increase the risk of dementia in PD. A total of 37 articles were included in the systematic review, in which 9 risk factors and 1 protective factor were additionally associated in single studies with the risk of PD with cognitive impairment, and 5 factors were associated with specific cognition domains. CONCLUSIONS: Effective interventions in the management of PD symptoms, comorbidities, and lifestyles may be promising to reduce PD with cognitive impairment risk. © 2019 International Parkinson and Movement Disorder Society.

TREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis.

TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer's disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder.

Inflammatory markers in Alzheimer's disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies.

OBJECTIVE: Inflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively. METHODS: Studies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity. RESULTS: A total of 170 studies were included in the meta-analysis and systematic review, which demonstrated increased peripheral levels of high-sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin-6 (IL-6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1-antichymotrypsin (α1-ACT) (1.217, p<0.005), IL-1ß (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL-10 (0.434, p<0.05), monocyte chemoattractant protein-1 (MCP-1) (0.798, p<0.005), transforming growth factor-beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL-40 (0.849, p<0.001), α1-ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin-like protein-1 (VILIP-1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL-6 (0.129, p<0.05) and MCP-1 (0.779, p<0.05) and lower levels of IL-8 (-1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL-40 (0.373, p<0.05), VILIP-1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI. CONCLUSION: Significantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

Midlife Modifiable Risk Factors for Dementia: A Systematic Review and Meta-analysis of 34 Prospective Cohort Studies.

OBJECTIVE: The aim of this study is to assess the association between midlife risk factors and dementia. METHODS: PubMed and Cochrane library were systematically searched on May 24, 2018, to retrieve prospective cohort studies. The summary Relative Risk (RR) and 95% Confidence Interval (CI) were calculated by the random-effect model to explore the association between midlife risk factors and dementia. Sensitivity analysis and meta-regression were conducted to explore the source of heterogeneity. Publication bias was examined using Begg's and Egger's tests. RESULTS: Thirty-four prospective cohort studies were included, among which 24 were eligible for metaanalysis. A total of 159,594 non-demented adults were enrolled at baseline before 65 years and 13,540 people were diagnosed with dementia after follow-up. The pooled results revealed that five factors could significantly increase the dementia risk by 41 to 78%, including obesity (RR, 1.78; 95% CI: 1.31-2.41), diabetes mellitus (RR, 1.69; 95% CI: 1.38-2.07), current smoking (RR, 1.61; 95%, CI: 1.32-1.95), hypercholesterolemia (RR, 1.57; 95% CI: 1.19-2.07), and hypertension (borderline blood pressure RR, 1.41; 95% CI: 1.23-1.62 and high Systolic Blood Pressure (SBP) RR, 1.72; 95% CI: 1.25-2.37). However, the sensitivity analyses found that the results of hypercholesterolemia and high SBP were not reliable, which need to be confirmed by more high-quality studies. No influences due to publication bias were revealed. In the systematic review, another three factors (hyperhomocysteinemia, psychological stress, and heavy drinking) were found to be associated with elevated dementia risk. In addition, physical exercise, a healthy diet, and hormone therapy in middle age were associated with the reduction of dementia risk. CONCLUSIONS: Middle-aged people with obesity, diabetes, hypertension, or hypercholesterolemia, and current smokers in midlife are at higher risk of developing dementia later in life.

Modifiable risk factors for carotid atherosclerosis: a meta-analysis and systematic review.

BACKGROUND: Carotid atherosclerosis is a major cause of stroke, but the conclusion about risk factors for carotid atherosclerosis is still controversial. The aim of our present meta-analysis and systematic review was to explore the modifiable risk factors for carotid atherosclerosis. METHODS: We searched PubMed from January 1962 to October 2018 to include longitudinal and cross-sectional studies. The results were pooled using random effects model. Heterogeneity was measured by I2 statistic and publication bias was assessed by funnel plots. RESULTS: A total of 14,700 articles were screened, of which 76 with 27 factors were eligible. Our meta-analysis of cross-sectional studies indicated nine factors (hyperlipidemia, hyperhomocysteinemia, hypertension, hyperuricemia, smoking, metabolic syndrome, hypertriglyceridemia, diabetes, and higher low density lipoprotein) were significantly associated with the presence of carotid plaque, among which four (hyperlipidemia, hyperhomocysteinemia, hypertension, and hyperuricemia) could elevate the risk of atherosclerosis by at least 50%; and one factor (hypertension) was associated with increased carotid intima-media thickness. In the systematic review, another five factors [negative emotion, socioeconomic strain, alcohol, air pollution, and obstructive sleep apnea syndrome (OSAS)] were also related to the presence of atherosclerosis. The cross-sectional associations with most of the above 14 factors were further confirmed by longitudinal studies. Among them, the managements of 4 factors (hypertension, hyperlipidemia, diabetes and OSAS) were indicated to prevent carotid atherosclerosis by cohort studies. CONCLUSIONS: Effective interventions targeting pre-existing disease, negative emotion, lifestyle and diet may reduce the risk of carotid atherosclerosis. Further good-quality prospective studies are needed to confirm these findings.

A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid.

α-Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain which plays a role in the regulation of neurotransmitter release, synaptic function, and plasticity, thus making it the focus in understanding the etiology of a group of neurodegenerative diseases. We conducted genome-wide association studies (GWAS) of α-synuclein levels in cerebrospinal fluid (CSF) with 209 non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort using a linear regression model to identify novel variants associated with α-synuclein concentration. The minor allele (T) of rs7072338 in the long intergenic non-protein coding RNA 1515 (LINC01515) and the minor allele (T) of rs17794023 in clusterin-associated protein 1 (CLUAP1) were associated with higher CSF α-synuclein levels at genome-wide significance (P = 4.167 × 10-9 and 9.56 × 10-9, respectively). In addition, single nucleotide polymorphisms (SNPs) near amyloid beta precursor protein (APP) (rs1394839) (P = 2.31 × 10-7), Rap guanine nucleotide exchange factor 1 (RAPGEF1) (rs10901091) (P = 8.07 × 10-7), and two intergenic loci on chromosome 2 and 14 (rs11687064 P = 2.50 × 10-7and rs7147386 P = 4.05 × 10-7) were identified as suggestive loci associated with CSF α-synuclein levels. We have identified significantly associated SNPs for CSF α-synuclein. These associations have important implications for a better understanding of α-synuclein regulation and allow researchers to further explore the relationships between these SNPs and α-synuclein-related neurodegenerative disorders.