Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
Animals ; Brain-Derived Neurotrophic Factor/metabolism* ; Cognitive Dysfunction/complications* ; DNA Methylation ; Homocysteine/metabolism* ; Hyperhomocysteinemia/metabolism* ; Rats ; Stress, Psychological/physiopathology*

BackgroundMemory complaint is common in the elderly. Recently, it was shown that self-report memory complaint was predictive of cognitive decline. This study aimed to investigate the predictive value of the source of memory complaints on the risk of cognitive impairment and cognitive decline in a community-based cohort.

MethodsData on memory complaints and cognitive function were collected among 1840 Chinese participants (aged ≥55 years old) in an urban community at baseline interview and 5-year follow-up. Incident cognitive impairment was identified based on education-adjusted Mini-Mental State Examination score. Logistic regression model was used to estimate the association between the source of memory complaints and risk of cognitive impairment conversion and cognitive decline, after adjusting for covariates.

ResultsA total of 1840 participants were included into this study including 1713 normal participants and 127 cognitive impairment participants in 2009. Among 1713 normal participants in 2009, 130 participants were converted to cognitive impairment after 5 years of follow-up. In 2014, 606 participants were identified as cognitive decline. Both self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment (odds ratio [OR] = 1.60, 95% confidence interval [CI]: 1.04-2.48) and cognitive decline (OR = 1.30, 95% CI: 1.01-1.68). Furthermore, this association was more significant in males (OR = 2.10, 95% CI: 1.04-4.24 for cognitive impairment and OR = 1.87, 95% CI: 1.20-2.99 for cognitive decline) and in higher education level (OR = 1.79, 95% CI: 1.02-3.15 for cognitive impairment and OR = 1.40, 95% CI: 1.02-1.91 for cognitive decline).

ConclusionsBoth self- and informant-reported memory complaints were associated with an increased risk of cognitive impairment conversion and cognitive decline, especially in persons with male gender and high educational background.

Aged ; Aged, 80 and over ; Cognition ; physiology ; Cognitive Dysfunction ; physiopathology ; Female ; Humans ; Logistic Models ; Male ; Memory ; physiology ; Middle Aged ; Neuropsychological Tests ; Odds Ratio

Singapore has an ageing population with a projected 53,000 people aged ≥ 60 years living with dementia by 2020. Primary care doctors have the opportunity to initiate early work-up for reversible causes of cognitive dysfunction, allowing identification of comorbidities and discussion of medical therapy options. Early diagnosis confers the sick role on the patient, which allays frustration and explains events and behaviour that may have strained relationships with family and friends. The patient can be encouraged to plan for future health and personal care options with a Lasting Power of Attorney and/or Advance Care Planning. Objective cognitive tests (e.g. abbreviated mental test and Mini-Mental State Examination) and brain imaging are adjuncts that help in formulating the diagnosis. Referral to a hospital memory clinic activates a multidisciplinary team approach to dementia, including clinical consultation, dementia counselling, physiotherapy sessions on gait/fall prevention, occupational therapy sessions on cognitive stimulation and caregiver training.
Advance Care Planning ; Aged ; Aged, 80 and over ; Brain ; physiopathology ; Caregivers ; Cognition ; Cognitive Dysfunction ; diagnosis ; epidemiology ; therapy ; Cognitive Therapy ; Dementia ; diagnosis ; epidemiology ; therapy ; Geriatrics ; methods ; Home Nursing ; Humans ; Interdisciplinary Communication ; Memory ; Middle Aged ; Neuropsychological Tests ; Referral and Consultation ; Singapore

OBJECTIVETo research Angelica tenuissima Nakai (ATN) for use in novel Alzheimer's disease (AD) therapeutics.

METHODSThe effect of a 30% ethanol extract of ATN (KH032) on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of β-amyloid (Aβ) peptide (Aβ) was investigated. Male C57Bl/6 mice were randomly divided into 4 groups, 10 in each group. KH032-treated groups were administrated with a low or high dose of KH032 (50 and 200 mg/kg, respectively), intragastrically for 16 days; distilled water was applied in the sham and negative groups. Open fifield test, Y maze and Morris water maze test were used for behavior test and cognitive ability. In addition, the neuroprotective effects of KH032 in Aβ-infused mice on the histopathological markers [neuronspecific nuclear protein (NeuN), Aβ] of neurodegeneration were examined. The levels of glial fibrillary acidic protein (GFAP), NeuN, phosphorylation extracellular signal-regulated kinase (ERK)/ERK, brain-derived neurotrophic factor (BDNF), phosphorylation cAMP response element-binding (CREB)/CREB protein expression were measured by Western blot.

RESULTSKH032 treatment ameliorated cognitive impairments, reduced the overexpression of Aβ, and inhibited neuronal loss and neuroinflammatory response in the Aβ-infused mice. Moreover, KH032 treatment enhanced BDNF expression levels in the hippocampus. Finally, KH032 treatment increased phosphorylation of ERK1/2 and CREB, vital for ERK-CREB signaling.

CONCLUSIONSKH032 attenuated cognitive defificits in the Aβ-infused mice by increasing BDNF expression and ERK1/2 and CREB phosphorylation and inhibiting neuronal loss and neuroinflflammatory response, suggesting that KH032 has therapeutic potential in neurodegenerative disorders such as AD.

Alzheimer Disease ; drug therapy ; pathology ; physiopathology ; Amyloid beta-Peptides ; Angelica ; chemistry ; Animals ; Brain ; pathology ; Brain-Derived Neurotrophic Factor ; metabolism ; Cognitive Dysfunction ; complications ; drug therapy ; physiopathology ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Disease Models, Animal ; Male ; Maze Learning ; drug effects ; Memory, Short-Term ; drug effects ; Mice, Inbred C57BL ; Neurogenesis ; drug effects ; Neuroglia ; drug effects ; metabolism ; pathology ; Neurons ; drug effects ; metabolism ; pathology ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Phosphorylation ; drug effects ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Plaque, Amyloid ; drug therapy ; pathology ; physiopathology ; Signal Transduction ; drug effects

The purpose of this study was to explore the differences in interhemispheric functional connectivity in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) based on a triple network model consisting of the default mode network (DMN), salience network (SN), and executive control network (ECN). The technique of voxel-mirrored homotopic connectivity (VMHC) analysis was applied to explore the aberrant connectivity of all patients. The results showed that: (1) the statistically significant connections of interhemispheric brain regions included DMN-related brain regions (i.e. precuneus, calcarine, fusiform, cuneus, lingual gyrus, temporal inferior gyrus, and hippocampus), SN-related brain regions (i.e. frontoinsular cortex), and ECN-related brain regions (i.e. frontal middle gyrus and frontal inferior); (2) the precuneus and frontal middle gyrus in the AD group exhibited lower VMHC values than those in the aMCI and healthy control (HC) groups, but no significant difference was observed between the aMCI and HC groups; and (3) significant correlations were found between peak VMHC results from the precuneus and Mini Mental State Examination (MMSE) and Montreal Cognitive Scale (MOCA) scores and their factor scores in the AD, aMCI, and AD plus aMCI groups, and between the results from the frontal middle gyrus and MOCA factor scores in the aMCI group. These findings indicated that impaired interhemispheric functional connectivity was observed in AD and could be a sensitive neuroimaging biomarker for AD. More specifically, the DMN was inhibited, while the SN and ECN were excited. VMHC results were correlated with MMSE and MOCA scores, highlighting that VMHC could be a sensitive neuroimaging biomarker for AD and the progression from aMCI to AD.
Aged ; Aged, 80 and over ; Alzheimer Disease/physiopathology* ; Brain/diagnostic imaging* ; Brain Mapping ; Cognitive Dysfunction/physiopathology* ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Memory ; Middle Aged ; Models, Neurological ; Nerve Net

Objective: To investigate the association between people who were under lack of care in childhood and the development of cognitive impairment in their middle-aged and elderly life spans. Methods: Based on the baseline survey data of the third phase of "Guangzhou Biobank Cohort study" conducted from January 2007 to January 2008, 9 223 residents aged ≥50 years with records on Mini Mental State Examination (MMSE) were included in a retrospective survey on received childhood care of their early lives. Questions would include: feelings of care and support from their close relatives during childhood, the status of separation from their mothers for ≥1 year, and the current status of their parents. Linear regression, unconditional and multinomial logistic regression models were used to analyze the associations between the received childhood care and cognitive function (i.e., MMSE scores and cognitive impairment) in middle and old age, of this population under study. Results: After adjusting for age, gender, education, place of residence, marital status, physical activity, smoking, drinking, occupation, personal income, childhood socioeconomic position and depressive symptoms etc., factors as feeling lack of concern and support from close relatives (LC), status of separation from the mother for ≥1 year (SM), and the current status of their parents etc., were all negatively associated with the MMSE score when in middle and old age, with partial regression coefficient β (95%CI) as -0.44 (-0.65- -0.23), -0.26 (-0.38- -0.14) and -0.61 (-0.96- -0.27), respectively. The presence of LC, SM or PD were associated with the increased risks of cognitive impairment, and the adjusted odds ratio OR (95%CI) appeared as 1.43 (1.15-1.78), 1.26 (1.08-1.47) and 1.64 (1.16-2.31) respectively in all the participants, but 1.27 (1.01-1.62), 1.29 (1.09-1.55) and 1.75 (1.19-2.55) respectively, in those with education level of primary school or below. In those with secondary school education or above, only the presence of item A was associated with an increased risk of cognitive impairment (OR=2.26, 95%CI: 1.41-3.50). Conclusion: We noticed that 'lack of care' in childhood was associated with cognitive impairment during middle and old age, mainly in those population with lower education.
Aged ; Cognition/physiology* ; Cognition Disorders/physiopathology* ; Cognitive Dysfunction/physiopathology* ; Humans ; Linear Models ; Middle Aged ; Odds Ratio ; Retrospective Studies ; Surveys and Questionnaires

To study the correlation between the spatial cognitive impairment and different subtypes of estrogen receptor α (ERα) of hippocampus in diabetic mice, we used alloxan (intraperitoneal injection) to induce type 1 diabetes in male Kunming mice and compared the spatial cognitive ability of the model mice with that of control mice through Morris water maze test. Meanwhile, using Western blot, we detected the protein expressions of ER-α36, ER-α66, caveolin-1, PKCα, cAMP-response element binding protein 2 (CREB2), and synaptophysin (Syn) in the hippocampus of the mice. The results showed that on the 3rd and 5th days of training, the ability of spatial learning and memory in the diabetic mice was significantly inferior to that of the control mice (P < 0.05). In the diabetic mice, the protein expressions of caveolin-1 and PKCα were decreased (P < 0.05), but ER-α66 expression was unaffected, while ER-α36 and CREB2 expressions were significantly increased (P < 0.05) compared with those of the control mice. The results suggest that abnormal expression of ER-α36 and related signal molecules may be important factors for diabetes-induced spatial cognitive impairment.
Animals ; Caveolin 1 ; metabolism ; Cognitive Dysfunction ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Diabetes Mellitus, Experimental ; physiopathology ; Estrogen Receptor alpha ; metabolism ; Hippocampus ; metabolism ; physiopathology ; Male ; Maze Learning ; Memory ; Mice ; Protein Kinase C-alpha ; metabolism ; Synaptophysin ; metabolism

BACKGROUNDPatients with Alzheimer's disease (AD) manifest progressive decline in writing abilities. Most studies on agraphia in AD have been performed in the alphabetic system, such as English. However, these findings may not be applicable to other written language systems. The unique features of the Chinese written script could affect the patterns of agraphia in Chinese AD patients. The aim of this study was to explore the features of writing errors in Chinese patients with AD and amnestic mild cognitive impairment (a-MCI), as well as to study the relationship between their writing errors and neuropsychological functions.

METHODSIn this study, we performed an observational study in a group of subjects including 17 AD patients, 14 patients with a-MCI, and 16 elderly healthy controls. We analyzed the writing errors in these subjects and also studied the relationship between their writing errors and neuropsychological functions.

RESULTSOur study showed that in patients whose mother tongue is Chinese, writing ability was comparatively well preserved in the MCI phase but significantly impaired when the disease progressed to the stage of AD. The writing errors showed corresponding increase with the severity of cognition decline, both in the types of errors and rate of occurrence. Analysis of the writing errors showed that word substitution and unintelligible words were the most frequent error types that occurred in all the three study groups. The occurrence rate of unintelligible words was significantly higher in the AD group compared with the a-MCI group (P = 0.024) and control group (P = 0.018). In addition, the occurrence rates of word substitution were also significantly higher in AD (P = 0.013) and a-MCI groups (P = 0.037) than that of control group. However, errors such as totally no response, visuospatial impairment, paragraph agraphia, ideograph, and perseverative writing errors were only seen in AD group. Besides, we also found a high occurrence rate of visuoconstructional errors (13.3%) in our AD group.

CONCLUSIONSOur study confirmed that agraphia is an important feature in patients with AD. The writing error profile in patients whose native language is Chinese was unique compared to patients using the alphabetic language system.

Aged ; Agraphia ; diagnosis ; physiopathology ; Alzheimer Disease ; complications ; physiopathology ; Asian Continental Ancestry Group ; Cognition Disorders ; diagnosis ; physiopathology ; Cognitive Dysfunction ; diagnosis ; physiopathology ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests

BACKGROUNDCognitive impairment is a severe complication caused by obstructive sleep apnea (OSA). The mechanisms of causation are still unclear. The Wnt/β-catenin signaling pathway is involved in cognition, and abnormalities in it are implicated in neurological disorders. Here, we explored the Wnt/β-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia (CIH), the most characteristic pathophysiological component of OSA.

METHODSWe divided 32 4-week-old male C57/BL mice into four groups of eight each: a CIH + normal saline (NS) group, CIH + LiCl group, sham CIH + NS group, and a sham CIH + LiCl group. The spatial learning performance of each group was assessed by using the Morris water maze (MWM). Protein expressions of glycogen synthase kinase-3β (GSK-3β) and β-catenin in the hippocampus were examined using the Western blotting test. EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used, respectively, to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region.

RESULTSMice exposed to CIH showed impaired spatial learning performance in the MWM, including increased mean escape latencies to reach the target platform, decreased mean times passing through the target platform and mean duration in the target quadrant. The GSK-3β activity increased, and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice. Besides, CIH significantly increased hippocampal neuronal apoptosis, with an elevated apoptosis index. Meanwhile, LiCl decreased the activity of GSK-3β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH.

CONCLUSIONSWnt/β-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCl might attenuate CIH-induced cognitive impairment via Wnt/β-catenin signaling pathway.

Animals ; Chronic Disease ; Cognitive Dysfunction ; etiology ; physiopathology ; Glycogen Synthase Kinase 3 beta ; physiology ; Hypoxia ; complications ; physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Wnt Signaling Pathway ; physiology ; beta Catenin ; physiology

INTRODUCTIONHyperfamiliarity, a phenomenon in which feelings of familiarity are evoked by novel stimuli, is well described in epilepsy and the lesioned brain. Abnormality of familiarity in Alzheimer's disease (AD) and mild cognitive impairment (MCI) have also been described in the literature, but more from a neuropsychological approach perspective. Currently, there is a lack of study on the real-life experience of familiarity abnormality in dementia and MCI. Our aim was to compare the occurrence of hyperfamiliarity among dementia and MCI.

MATERIALS AND METHODSWe recruited 73 participants, 29 with AD, 10 with vascular dementia, 7 with MCI and 27 healthy controls, and administered a questionnaire to assess hyperfamiliarity frequency.

RESULTSHyperfamiliarity was observed in real-life in cognitive impairment, but was unrelated to its severity or underlying aetiology.

CONCLUSIONThis study highlights the similar rate of occurrence of hyperfamiliarity in the daily life of individuals with cognitive impairment. Future research should examine neuropsychological correlations and mechanisms that contribute to such observations.

Aged ; Aged, 80 and over ; Alzheimer Disease ; physiopathology ; psychology ; Case-Control Studies ; Cognitive Dysfunction ; physiopathology ; psychology ; Dementia ; physiopathology ; psychology ; Dementia, Vascular ; physiopathology ; psychology ; Female ; Humans ; Male ; Middle Aged ; Recognition (Psychology) ; Severity of Illness Index ; Singapore