Pathogenesis Of Mild Cognitive Impairment Research Articles

Investigating the association between inflammation mediated by mushroom consumption and mild cognitive impairment in Chinese older adults.

Background: Chronic inflammatory stimulation is a major risk factor for mild cognitive impairment. Mushroom consumption and inflammatory factors may play an important role in the pathogenesis of mild cognitive impairment. Additionally, consuming mushrooms can reduce the levels of inflammatory cytokines and preserve cognitive function. Therefore, this study aimed to investigate the relationship between mushroom consumption and serum inflammatory cytokines and mild cognitive impairment (MCI). Methods: Binary logistic regression was used to determine the relationship between mushroom consumption and MCI in 550 participants. Subsequently, mediation analysis was used to analyze the relationship between mushroom consumption, inflammatory factors, and the Montreal Cognitive assessment (MoCA) score in 248 participants. Results: Mushroom consumption was associated with MCI (odds ratio = 0.623, 95% confidence interval = 0.542-0.715, P < 0.001). The association between mushroom intake and MCI was mediated by interleukin-6 (IL-6) and hypersensitive C-reactive protein (hs-CRP), and the MoCA score was 12.76% and 47.59%, respectively. Conclusion: A high intake of mushrooms was associated with a low risk of MCI. Serum inflammatory factors including IL-6 and hs-CRP play a partial mediating role between mushroom intake and the MoCA score, and the underlying mechanism needs to be further explored.

Bartonella spp. infection in people with Mild Cognitive Impairment: A pilot study.

Mild Cognitive Impairment (MCI) is a neurological disorder at the transition between normal cognitive decline and dementia. Despite the potential role of neuroinflammation in the pathogenesis of MCI, infectious triggers remain mostly unknown. Infection with Bartonella spp., a zoonotic bacterium, has recently been associated with diffuse neurological and psychiatric symptoms. Given the preferential endothelial localization of Bartonella spp. and the role of vascular changes in neurocognitive decline, we hypothesized that there is an association between Bartonella spp. infection and pathologically accelerated decline in cognitive function in aging. To test this hypothesis, we collected serological and molecular markers of past and present Bartonella spp. infection in a sample of older people with and without MCI. Samples were processed in a blinded way to exclude laboratory biases. Contrary to our hypothesis, people with MCI were not more likely than people without MCI to have an active Bartonella spp. infection as measured by droplet digital PCR (p = 0.735) and quantitative PCR (p = 1). In addition, there was no significant difference in positive serological results between cases and controls (p = 0.461). Overall, higher-than-expected active Bartonella spp. infection (37% by ddPCR) and seroreactivity (71% by indirect fluorescent antibody assay) were found in people without MCI. Conclusions require caution, as our study was limited by the small number of cases with MCI. Overall, our results identified a higher than previously recognized rate of exposure and infection with Bartonella spp. in this older study population but does not support a specific role for such infection in MCI.

Levels of chemokines and other inflammatory mediators in patients with mild cognitive impairment undergoing rehabilitation

Alzheimer's disease is the most common neurodegenerative disease in old age. In some cases, it is preceded by mild cognitive impairment (MCI). One of the important components in the pathogenesis of neurodegeneration is chronic neuroinflammation (inflammatory activation of microglia and astrocytes in the brain). Systemic inflammatory response and immune dysregulation may contribute to neuroinflammation. The purpose of this study was to investigate the level of chemokines and other inflammatory mediators in patients with MCI who underwent medical rehabilitation, and to study its associations with the severity of cognitive impairment. The study group included 48 patients with MCI undergoing rehabilitation. Rehabilitation included cognitive therapy, psychotherapy and tasks for unaided performance. Repeated examination was conducted 6 months after the completion of rehabilitation. The control group included 46 healthy volunteers. Multiplex assay was used to determine serum cytokine and chemokine concentrations. Student's t-test was used to assess the significance of differences. Assessment of cognitive functions was performed using international neuropsychological scales. In patients with MCI, we have found an increase in the levels of several cytokines and chemokines (TNFα, CXCL10/IP10, MDC) that regulate systemic inflammation, cellular and humoral mechanisms of adaptive immunity. After the rehabilitation course their levels returned to normal. It was also found that decrease in CCL7 level in the patients before the rehabilitation course is associated with the severity of cognitive impairment. The findings contribute to understanding the role of chemokines in the pathogenesis of MCI, and indicate that their levels can be potential biomarkers of the severity of cognitive impairment. For translation of the findings into clinical practice, their validation in larger studies is needed, as well as assessing the associations between chemokine levels and the severity of cognitive impairment in MCI over long-term follow-up.

Telomere and mitochondria mediated the association between dietary inflammatory index and mild cognitive impairment: A prospective cohort study

BackgroundDiet and chronic inflammation might play a major role in the pathogenesis of mild cognitive impairment (MCI). In addition, peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) might mediate the relationship between inflammation and MCI risk. The purpose of the present study is to evaluate whether inflammatory potential of diet assessed by dietary inflammatory index (DII), chronic inflammation, peripheral blood LTL, and mtDNAcn were associated with the risk of MCI.ResultsA population-based cohort study was conducted with a total of 2944 participants. During a median follow-up of 2 years, 438 (14.90%) individuals were new-onset MCI. After adjustment, a higher score of DII (hazard ratio [HR]: 1.056, 95% CI: 1.005, 1.109), a higher log systemic immune inflammation index (SII) (HR: 1.333, 95% CI: 1.089, 1.633) and log system inflammation response index (SIRI) (HR: 1.487, 95% CI: 1.024, 2.161) predicted elevated risk of MCI. An increased mtDNAcn (HR: 0.843, 95% CI: 0.712, 0.997), but not LTL, predicted a decreased risk of MCI. Negative associations of log SII with LTL (β:-0.359, 95% CI: -0.445, -0.273) and mtDNAcn (β:-0.048, 95% CI: -0.090, -0.006) were found. Additionally, negative associations of log SIRI with LTL (β: -0.035, 95% CI: -0.052, -0.017) and mtDNAcn (β:-0.136, 95% CI: -0.216, -0.056) were also found. Path analysis suggested that SIRI, LTL, and mtDNAcn, in series, have mediation roles in the association between DII score and MCI risk.ConclusionsHigher DII, SII, and SIRI might predict a greater risk of MCI, while a longer LTL and an increased mtDNAcn were linked to a reduced risk of MCI among the older population. LTL and mtDNAcn could play mediation roles in the association between DII and MCI risk.

Investigation of the functional pathogenesis of mild cognitive impairment by localisation-based locus coeruleus resting-state fMRI.

Dementia as one of the most prevalent diseases urges for a better understanding of the central mechanisms responsible for clinical symptoms, and necessitates improvement of actual diagnostic capabilities. The brainstem nucleus locus coeruleus (LC) is a promising target for early diagnosis because of its early structural alterations and its relationship to the functional disturbances in the patients. In this study, we applied our improved method of localisation-based LC resting-state fMRI to investigate the differences in central sensory signal processing when comparing functional connectivity (fc) of a patient group with mild cognitive impairment (MCI, n=28) and an age-matched healthy control group (n=29). MCI and control participants could be differentiated in their Mini-Mental-State-Examination (MMSE) scores (p < .001) and LC intensity ratio (p=.010). In the fMRI, LC fc to anterior cingulate cortex (FDR p < .001) and left anterior insula (FDR p=.012) was elevated, and LC fc to right temporoparietal junction (rTPJ, FDR p=.012) and posterior cingulate cortex (PCC, FDR p=.021) was decreased in the patient group. Importantly, LC to rTPJ connectivity was also positively correlated to MMSE scores in MCI patients (p=.017). Furthermore, we found a hyperactivation of the left-insula salience network in the MCI patients. Our results and our proposed disease model shed new light on the functional pathogenesis of MCI by directing to attentional network disturbances, which could aid new therapeutic strategies and provide a marker for diagnosis and prediction of disease progression.

ASSOCIATION BETWEEN APOE-ε4 CARRIER STATUS AND QUALITATIVE NEUROIMAGING CHARACTERISTICS IN OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT.

The pathogenesis of mild cognitive impairment (MCI) is multifactorial and includes the presence of genetic variants such as the ε4 allele of the apolipoprotein E gene (APOE-ε4). Association between the APOE-ε4 carrier status and deleterious structural and functional changes on magnetic resonance imaging (MRI) has been previously described in individuals with Alzheimer's disease. However, the central nervous system changes may possibly develop in earlier stages of cognitive impairment, as reflected in MCI. The objective of the study was to determine the association between APOE-ε4 carrier status and qualitative changes on MRI (medial temporal and parietal atrophy), as well as the detection of white matter hyperintensities (WMH) in older adults with MCI, in the memory clinic of a tertiary care hospital in Mexico City. A cross-sectional study of 72 adults aged 60 years or above who underwent an exhaustive clinical, neuroimaging, and neuropsychological evaluation. Multivariate logistic regression models were constructed to determine the association between APOE-ε4 carrier status and qualitative/quantitative changes on MRI. Mean age was 75.2 years (± 7.2) and 64% were female. Twenty-one participants were cognitively normal and 51 had MCI. Almost 56% were APOE-ε4 carriers and were associated with medial-temporal atrophy according to the Scheltens scale (odds ratio [OR]: 20.0, 95% confidence intervals [CI]: 3.03-131.7), parietal atrophy according to the Koedam's score (OR: 6.3; 95% CI 1.03-39.53), and WMH according to the Fazekas scale (OR: 11.7, 95% CI: 1.26-108.2), even after adjusting for age, educational level, and cardiovascular risk factors. The APOE-ε4 carrier status was associated with medial temporal and parietal atrophy, as well as WMH. Our findings support the hypothesis suggesting the contribution of this genotype to neurodegeneration and cerebral vascular pathology.

Molecular Changes in Circulating microRNAs' Expression and Oxidative Stress in Adults with Mild Cognitive Impairment: A Biochemical and Molecular Study.

BackgroundThe release of miRNAs in tissue fluids significantly recommends its use as non-invasive diagnostic biomarkers for the progression and pathogenesis of mild cognitive impairment (MCI) in aged patients.ObjectiveThe potential role of circulated miRNAs in the pathogenesis of MCI and its association with cellular oxidative stress, apoptosis, and circulated BDNF, Sirtuin 1 (SIRT1), and dipeptidyl peptidase-4 (DPP4) were evaluated in older adults with MCI.MethodsA total of 150 subjects aged 65.4±3.7 years were recruited in this study. The participants were classified into two groups: healthy normal (n=80) and MCI (n=70). Real-time PCR analysis was performed to estimate the relative expression of miRNAs; miR-124a, miR-483-5p, miR-142-3p, and miR-125b, and apoptotic-related genes Bax, Bcl-2, and caspase-3 in the sera of MCI and control subjects. In addition, oxidative stress parameters; MDA, NO, SOD, and CAT; as well as plasma DPP4 activity, BDNF, SIRT1 levels were colorimetrically estimated.ResultsThe levels of miR-124a and miR-483-5p significantly increased and miR-142-3p and miR-125b significantly reduced in the serum of MCI patients compared to controls. The expressed miRNAs significantly correlated with severe cognitive decline, measured by MMSE, MoCA, ADL, and memory scores. The expression of Bax, and caspase-3 apoptotic inducing genes significantly increased and Bcl-2 antiapoptotic gene significantly reduced in MCI subjects compared to controls. In addition, the plasma levels of MDA, NO, and DPP4 activity significantly increased, and the levels of SOD, CAT, BDNF, and SIRT1 significantly reduced in MCI subjects compared to controls. The expressed miRNAs correlated positively with NO, MDA, DPP4 activity, BDNF, and SIRT-1, and negatively with the levels of CAT, SOD, Bcl-2, Bax, and caspase-3 genes.ConclusionCirculating miR-124a, miR-483-5p, miR-142-3p, and miR-125b significantly associated with severe cognitive decline, cellular oxidative stress, and apoptosis in patients with MCI. Thus, it could be potential non-invasive biomarkers for the diagnosis of MCI with high diagnostic performance.

Inflammatory markers in Alzheimer's disease and mild cognitive impairment: A meta‐analysis and systematic review of 170 studies

AbstractBackgroundInflammation 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.MethodStudies 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.ResultA 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&lt;0.05), interleukin‐6 (IL‐6) (0.429, p&lt;0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p&lt;0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p&lt;0.005), alpha1‐antichymotrypsin (α1‐ACT) (1.217, p&lt;0.005), IL‐1β (0.615, p&lt;0.05) and soluble CD40 ligand (0.868, p&lt;0.005), and CSF levels of IL‐10 (0.434, p&lt;0.05), monocyte chemoattractant protein‐1 (MCP‐1) (0.798, p&lt;0.005), transforming growth factor‐beta 1 (1.009, p&lt;0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p&lt;0.001), YKL‐40 (0.849, p&lt;0.001), α1‐ACT (0.638, p&lt;0.001), nerve growth factor (5.475, p&lt;0.005) and visinin‐like protein‐1 (VILIP‐1) (0.677, p&lt;0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p&lt;0.05), IL‐6 (0.129, p&lt;0.05) and MCP‐1 (0.779, p&lt;0.05) and lower levels of IL‐8 (‐1.293, p&lt;0.05) in the periphery, as well as elevated concentrations of YKL‐40 (0.373, p&lt;0.05), VILIP‐1 (0.534, p&lt;0.005) and sTREM2 (0.695, p&lt;0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p&lt;0.05) and sTNFR2 (0.254, p&lt;0.05) levels were observed in AD compared with MCI.ConclusionSignificantly 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.

The method and effect of rapid establishment of a mild cognitive impairment model

To further the exploration of the pathogenesis of mild cognitive impairment (MCI), we aimed to determine the appropriate dose for a rapidly established MCI rat model using D-galactose (D-gal), with lasting cognitive effects. In Experiment 1, we evaluated various D-gal concentrations (100-2,000 mg/kg/day), and determined that, compared with saline injections of the same volume. In Experiment 2, we evaluated the duration of the effect of 1,000 mg/kg/day D-gal injections for 1 week, with MWM testing initiated at 1 day, 1 month, and 3 months after completion of the injection regime in three model groups, respectively. In Experiment 1, D-gal injections at a concentration of 1,000 mg/kg/day for 1 week was adequate to induce a significantly worse Morris water maze (MWM) test performance and pathomorphologic changes in the hippocampus, with MWM testing initiated 1 day after completion of the injection regime. In Experiment 2, Before modeling, the overall condition (fur, mental state, foraging behavior, and activity level), body weight, swimming speed, and swimming time did not significantly differ between the control (saline injections) and model groups (D-gal injections). After modeling, MWM test performance was considerably worse (longer escape latencies and fewer platform crossings within 90 seconds) in the model groups than in the control group, without significant differences among model groups. Furthermore, movement trajectories were similar among model groups. These results demonstrate that subcutaneous injections of D-gal 1,000 mg/kg/day for 1 week produce changes consistent with the characteristics and pathological processes of MCI. Thus, high-dose D-gal injection allows the rapid establishment of an MCI model that is effective and sustainable.

A pilot study of brain morphometry following donepezil treatment in mild cognitive impairment: volume changes of cortical/subcortical regions and hippocampal subfields

The efficacy of donepezil is well known for improving the cognitive performance in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Most of the recent neuroimaging studies focusing on the brain morphometry have dealt with the targeted brain structures, and thus it remains unknown how donepezil treatment influences the volume change over the whole brain areas including the cortical and subcortical regions and hippocampal subfields in particular. This study aimed to evaluate overall gray matter (GM) volume changes after donepezil treatment in MCI, which is a prodromal phase of AD, using voxel-based morphometry. Patients with MCI underwent the magnetic resonance imaging (MRI) before and after 6-month donepezil treatment. The cognitive function for MCI was evaluated using the questionnaires of the Korean version of the mini-mental state examination (K-MMSE) and Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog). Compared with healthy controls, patients with MCI showed significantly lower GM volumes in the hippocampus and its subfields, specifically in the right subiculum and left cornu ammonis (CA3). The average scores of K-MMSE in patients with MCI improved by 8% after donepezil treatment. Treated patients showed significantly higher GM volumes in the putamen, globus pailldus, and inferior frontal gyrus after donepezil treatment (p < 0.001). However, whole hippocampal volume in the patients decreased by 0.6% after 6-month treatment, and the rate of volume change in the left hippocampus was negatively correlated with the period of treatment. These findings will be useful for screening and tracking MCI, as well as understanding of the pathogenesis of MCI in connection with brain morphometric change.

Increased Plasma Dipeptidyl Peptidase-4 Activities Predict Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients: Findings from the GDMD Cohort Study in China

Background: Dipeptidyl peptidase-4(DPP4) is a newly identified adipokine that has been proved to promote hyperglycemia, insulin resistance, oxidative stress and inflammation, all of which have been involved in the pathogenesis of mild cognitive impairment (MCI). Hence, we examined whether increased DPP4 activity was associated with prospective risk of MCI and determined whether this association was mediated by these four risk factors in elderly type 2 diabetic patients. Methods: Baseline plasma DPP4 activity, HOMA of insulin resistance (HOMA-IR), oxidative stress parameters, inflammatory markers and long-term glycemic control were ascertained in a cohort of elderly type 2 diabetic patients aged>60 years (n = 2,066), along with questionnaire findings, biochemical measurements and MCI diagnoses. Prospective associations of baseline DPP4 activity and MCI events and its possible mediators were determined by Cox regression and mediation analyses. Findings: Over a median follow-up of 4.8 years, 367 patients (17.8 %) were diagnosed with MCI. Higher baseline DPP4 activity, IL-6, CRP, nitrotyrosine and 8-iso-PGF2a were independent predictors of MCI after adjustment (P<0.001). Furthermore, IL-6, CRP, nitrotyrosine and 8-iso-PGF2a all had statistically significant mediating effects on DPP4 activity-associated MCI incidence (P<0.05). We did not find a positive association between baseline HOMA-IR, average HbA1c and MCI incidence. Interpretation: Our results suggest that increased plasma DPP4 activity is an independent risk factor for incident MCI, and this association appears to be partially mediated by oxidative stress and inflammation, not insulin resistance or long-term glycemic control, both of which might not be able to predict MCI as well. Trial Registration: Registered on the Chinese clinical trial registry (ChiCTR-EPC-14005273). Funding Statement: This study was supported by grants from National Natural Science Foundation of China (Grant NO. 81770829 and NO. 81560144), Scientific Research and Technology Development Projects of Science and Technology Department of Guangxi province (Grant NO.1598012-13), Natural Science Foundation of Guangxi Province (Grant NO. 2015GXNSFBA139119) and High-Level Medical Talents Training Program of Guangxi Province (G201903002). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The GDMD Study was approved by the institutional medical ethical committee at Affiliated Hospital of Guilin Medical University. All participants gave written informed consent before data collection.

Identification of inflammatory and vascular markers associated with mild cognitive impairment.

Biochemical processes have been associated with the pathogenesis of mild cognitive impairment (MCI) and dementia, including chronic inflammation, dysregulation of membrane lipids and disruption of neurotransmitter pathways. However, research investigating biomarkers of these processes in MCI remained sparse and inconsistent. To collect fresh evidence, we evaluated the performance of several potential markers in a cohort of 57 MCI patients and 57 cognitively healthy controls. MCI patients showed obviously increased levels of plasma TNF-α (p = 0.045) and C-peptide (p = 0.004) as well as decreased levels of VEGF-A (p = 0.042) and PAI-1 (p = 0.019), compared with controls. In addition, our study detected significant correlations of plasma sTNFR-1 (MCI + Control: B = -6.529, p = 0.020; MCI: B = -9.865, p = 0.011) and sIL-2Rα (MCI + Control: B = -7.010, p = 0.007; MCI: B = -11.834, p = 0.003) levels with MoCA scores in the whole cohort and the MCI group. These findings corroborate the inflammatory and vascular hypothesis for dementia. Future studies are warranted to determine their potential as early biomarkers for cognitive deficits and explore the related mechanisms.

The Relationship Between Plasma DPP4 Activity to BDNF Ratio and Mild Cognitive Impairment in Elderly Population With Normal Glucose Tolerance.

Objective: Since decreased brain-derived neurotrophic factor (BDNF) and increased dipeptidyl peptidase-4 (DPP4) activity have both been implicated in the pathogenesis of mild cognitive impairment (MCI), the aim of our study was to evaluate the association of MCI with plasma DPP4 activity to BDNF ratio (DBR) in an elderly population with normal glucose tolerance.Methods: We cross-sectionally measured C-reactive protein, interleukin-6, nitrotyrosine, 8-iso-PGF2a, DPP4 activity BDNF and calculated the DBR in a total of 1,066 elderly participants in China. MCI was determined by the Montreal Cognitive Assessment and finally confirmed by neurologists.Results: An inverse correlation was found between DPP4 activity and BDNF (r = -0.456, P < 0.001) and this inverse correlation was partly mediated by nitrotyrosine and 8-iso-PGF2a. Across rising quartiles of DBR, nitrotyrosine, 8-iso-PGF2a, C-reactive protein and interleukin-6 progressively increased, whereas the Montreal Cognitive Assessment score progressively decreased. Subjects in the lowest quartile of BDNF and highest quartiles of DBR and DPP4 activity, had higher MCI risk compared with subjects in the highest quartile of the BDNF and lowest quartiles of DBR and DPP4 activity, respectively (all P < 0.05). The odds ratio for MCI became more pronounced with decreased BDNF and increased DPP4.Conclusion: In conclusion, a negative correlation was found between DPP4 activity and BDNF, and this negative correlation was partly mediated by oxidative stress, not inflammation. The DBR was positively associated with MCI and thus may be used as a novel risk biomarker for MCI in an elderly population with normal glucose tolerance.

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

ObjectiveInflammation 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...

P 236 - Oxidative Stress Markers of Alzheimer's Disease in Peripheral Cell Mitochondria

Alzheimer's disease (AD) represents a neurodegenerative disease leading to progressive dementia in the elderly. AD has been associated with increased oxidative stress and mitochondrial dysfunction. Hence, markers for oxidative stress are expected to accumulate not only in brain mitochondria, but also in mitochondria of peripheral cells. We have developed and optimized a method for the rapid and selective fluorogenic derivatization and enrichment of specific protein oxidation products, 3-nitrotyrosine and 3,4-dihydroxyphenylalanine (DOPA), in order to quantitatively compare protein oxidation in the mitochondria of peripheral, white blood cells obtained from healthy donors, patients with mild cognitive impairment (MCI), and AD patients. Double blind studies reveal a ca. two-fold increase of protein nitration/oxidation between mitochondrial proteins derived from healthy volunteers and MCI patients, with no further increase between MCI and AD patients. Proteomic studies will show whether specific proteins are target for nitration/oxidation during the pathogenesis of MCI and AD. Mitochondrial protein nitration/oxidation may be used for early screening of patients with the genetic risk for the development of AD or as companion diagnostic for pharmacological interventions.

Decreased Serum IGF-1/IGFBP-3 Molar Ratio is Associated with Executive Function Behaviors in Type 2 Diabetic Patients with Mild Cognitive Impairment

Insulin-like growth factor (IGF)-1, through insulin/IGF-1 signaling pathway, is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer's disease. This study aimed to assess the association of serum IGF-1 and IGF binding protein (IGFBP)-3 levels with cognition status and to determine whether IGF-1 rs972936 polymorphism is associated with T2DM with mild cognitive impairment (MCI). A total of 150 T2DM patients, 75 satisfying the MCI diagnostic criteria and 75 exhibiting healthy cognition, were enrolled in this study. The cognitive function of the subjects was extensively assessed. Serum IGF-1 and IGFBP-3 levels were measured through enzyme-linked immunosorbent assay; IGF-1/IGFBP-3 molar ratio was calculated. Single nucleotide polymorphisms of the IGF-1-(rs972936) gene were analyzed. Serum IGF-1/IGFBP-3 molar ratio in MCI patients was significantly lower than that in the control group (p = 0.003). Significant negative correlations were found between IGF-1/IGFBP-3 molar ratio and Trail Making Test A and B (TMT-A and TMT-B) scores (p = 0.003; p < 0.001, respectively), which indicated executive function. Further multiple step-wise regression analysis revealed that the TMT-A or TMT-B score was significantly associated only with serum IGF-1/IGFBP-3 molar ratio (p = 0.016; p < 0.001, respectively). No significant difference was found in the genotype or allele distribution of IGF-1 rs972936 polymorphism between MCI and control groups. A low serum IGF-1/IGFBP-3 molar ratio is associated with the pathogenesis of MCI, particularly executive function in T2DM populations. Further investigation with a large population size should be conducted to confirm this observed association.

Thyroid Status and Cognitive Function in Euthyroid Patients with Early Parkinson's Disease

Background: Alterations in thyroid hormone (TH) levels may be related to the pathogenesis of mild cognitive impairment (MCI) and dementia. Cognitive deficits are common in Parkinson's disease (PD) patients. The aim of this study was to investigate whether variations within the normal ranges of thyroid function are related to cognitive function in early PD without dementia. Methods: Eighty-four euthyroid patients with early PD underwent evaluation of their thyroid status, including measures of thyroid-stimulating hormone (TSH), total triiodothyronine (tT₃) and free thyroxine (fT₄), and comprehensive neuropsychological tests. Results: The 46 patients of the PD-MCI group did not differ in the serum levels of TH compared to the 38 patients of the PD-normal cognition group. fT₄ levels were inversely associated with the Mini-Mental State Examination (MMSE) score and neuropsychological tests of attention and visuospatial and executive function. TSH and tT₃ levels were not related to cognitive performances. After controlling for demographic and clinical variables, multiple regression analyses indicated statistically significant associations between fT₄ concentrations and MMSE score and neuropsychological tests of executive function. Conclusions: This study supports a relationship between the thyroid status and cognitive function in euthyroid early PD patients, with higher concentrations of fT₄ being associated with a poor performance of executive function.

Autonomic dysfunction in mild cognitive impairment: a transcranial Doppler study

The contribution of early microvascular and autonomic derangements to the pathogenesis of mild cognitive impairment (MCI) is unclear. Aim of this study is to evaluate cerebrovascular reactivity (CVR) and cardiac autonomic function in patients with MCI by means of transcranial Doppler (TCD). Fifteen patients with MCI and 28 controls underwent carotid ultrasound and TCD evaluation, including assessment of mean flow velocity (MFV) in the middle cerebral artery at baseline, after CO(2) inhalation and after hyperpnoea. End-tidal CO(2) , mean arterial blood pressure (MAP), heart rate (HR), and respiratory rate were monitored throughout the procedure, and CVR was calculated. MAP, end-tidal CO(2) , and MFV variations during hypercapnia and hyperventilation showed no between-group differences. CVR was similar in controls and MCI (2.30 vs 2,39, respectively, P = 0.767). HR significantly increased in hypercapnia (+9.4%, P < 0.0001) and hyperventilation (+18.7%, P < 0.0001) in controls, while in MCI it significantly increased in hyperventilation (+10.4%, P = 0.002), but not in hypercapnia (+1.1%, P = 0.635). This study demonstrates that patients with MCI have a normal CVR, but they exhibit signs of autonomic dysfunction after CO(2) challenge. Should this finding be confirmed in larger studies, HR response to CO(2) challenge could become a marker of MCI.

Association of arteriosclerosis with mild cognitive impairment in type 2 diabetics

Montreal cognitive assessment（MoCA, Beijing Version） was chosen as cognition assessment implement. 63 patients suffering from type 2 diabetes mellitus with mild cognitive impairment （MCI） were chosen to form a research group, and 27 patients with type 2 diabetes mellitus and normal cognitive function served as a control group. It was found that atherosclerosis played an important role in the pathogenesis of MCI in type 2diabetes, therefore, early prevention and management of atherosclerosis may help to improve the cognitive function. Key words: Diabetes mellitus, type 2; Mild cognitive impairment; Montreal cognitive assessment; Dementia ; Arteriosclerosis

Thyroid Hormones Are Associated with Poorer Cognition in Mild Cognitive Impairment

Background: Alterations in interrelated endocrine axes may be related to the pathogenesis of mild cognitive impairment (MCI) and dementia. Methods: Salivary cortisol before and after a 0.5-mg dexamethasone test, and serum levels of thyroid-stimulating hormone, total thyroxine (T₄), free T₄, total triiodothyronine (TT₃), estradiol, testosterone and insulin-like growth factor 1 were measured in 43 MCI cases and 26 healthy controls. All participants underwent a comprehensive neuropsychological test battery covering the cognitive domains of speed/attention, memory, visuospatial functions, language and executive functions. Results: The MCI group did not differ in basal levels of endocrine markers compared to controls. Among those with MCI, TT₃ levels were inversely associated with cognitive performance across all domains. After stratifying MCI cases according to TT₃ levels, those with relatively high TT₃ levels showed impairment in memory as well as in visuospatial and executive functions. Those with TT₃ levels at or below the lower boundary of the normal range performed comparably to healthy controls. Other endocrine markers were not related to cognitive performance. Conclusions: Among those with MCI, TT₃ was associated with a neuropsychological profile typical of prodromal Alzheimer’s disease. While the mechanisms remain unclear, optimal levels of thyroid hormone under a compromising condition such as MCI and related neuropathology need reconsideration.