The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

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.

Circulating polyunsaturated fatty acids, fish oil supplementation, and risk of incident dementia: a prospective cohort study of 440,750 participants.

Cohort studies report inconsistent associations between omega-3 polyunsaturated fatty acids (n-3 PUFA) or fish oil and dementia risk. Furthermore, evidence relating omega-6 polyunsaturated fatty acids (n-6 PUFA) with dementia is scarce. Here, we included 440,750 dementia-free participants from UK Biobank to comprehensively investigate the associations between plasma levels of different types of PUFA, fish oil supplementation, and dementia risk. During a median follow-up of 9.25 years, 7768 incident dementia events occurred. Higher plasma levels of five PUFA measures showed consistent associations with lower dementia risk (hazard ratios [95% confidence intervals] for per standard deviation increment of plasma concentrations 0.85 [0.81-0.89] for total PUFAs; 0.90 [0.86-0.95] for omega-3 PUFAs; 0.92 [0.87-0.96] for docosahexaenoic acid (DHA); 0.86 [0.82-0.90] for omega-6 PUFAs; 0.86 [0.82-0.90] for linoleic acid (LA); all p < 0.001). Compared with non-users, fish oil supplement users had a 7% decreased risk of developing all-cause dementia (0.93 [0.89-0.97], p = 0.002), and the relationship was partially mediated by plasma n-3 PUFA levels (omega-3 PUFAs: proportion of mediation = 57.99%; DHA: proportion of mediation = 56.95%). Furthermore, we observed significant associations of plasma n-3 PUFA levels and fish oil supplementation with peripheral immune markers that were related to dementia risk, as well as the positive associations of plasma PUFA levels with brain gray matter volumes and white matter microstructural integrity, suggesting they may affect dementia risk by affecting peripheral immunity and brain structure. Taken together, higher plasma PUFA levels and fish oil supplementation were associated with lower risk of incident dementia. This study may support the value of interventions to target PUFAs (specifically n-3 PUFAs) to prevent dementia.

Tea consumption and risk of incident dementia: A prospective cohort study of 377 592 UK Biobank participants.

As a widely consumed beverage, tea boasts diverse health benefits. Herein, we aimed to investigate the association between tea consumption and dementia risk. We conducted a prospective cohort study with 377 592 UK Biobank participants during a 9-year follow-up. Cox regression models adjusted for age, sex, ethnicity, Townsend deprivation index, education, body mass index, lifestyle factors, dietary factors and apolipoprotein E4 status were used to examine the association of tea consumption with dementia risk. Subgroup analyses stratified by age, sex and forms of dementia (Alzheimer's disease [AD] and vascular dementia [VD]) were performed. Moreover, the restricted cubic splines were used to calculate the nonlinear relationship between daily dosage of tea and dementia risk. After adjustment for all covariates, tea drinkers were 16% (95% confidence interval: 8-23) less likely to develop dementia compared with non-drinkers. Moderate consumption (1-6 cups/day) of tea exerted significant protective effects. Subgroup analyses showed that mid-aged participants or males benefited more from tea consumption. Moreover, moderate drinkers had a 16-19% lower hazard of AD and a 25-29% lower hazard of VD. Furthermore, a U-shaped association between tea consumption and dementia risk was shown (Pnon-linearity = 7E-04), and the consumption of around three cups per day showed the strongest protective effect. Within 3 cups/day, drinking one extra cup of tea per day brought a 6% reduction of incidence. In conclusion, moderate consumption of tea was significantly associated with a reduced risk of dementia, suggesting that tea consumption could be a modifiable lifestyle factor for dementia.

Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial.

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied.

Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer's disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. OBJECTIVE: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. METHODS: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOEɛ4 status and gender using a two-way analysis of covariance. RESULTS: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-ß 42 (Aß42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aß42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aß42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOEɛ4 and gender. CONCLUSION: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.

Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aß) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis.

BACKGROUND: Research into Ginkgo biloba has been ongoing for many years, while the benefit and adverse effects of Ginkgo biloba extract EGb761 for cognitive impairment and dementia has been discussed controversially. OBJECTIVE: To discuss new evidence on the clinical and adverse effects of standardized Ginkgo biloba extract EGb761 for cognitive impairment and dementia. METHODS: MEDLINE, EMBASE, Cochrane, and other relevant databases were searched in March 2014 for eligible randomized controlled trials of Ginkgo biloba EGb761 therapy in patients with cognitive impairment and dementia. RESULTS: Nine trials met our inclusion criteria. Trials were of 22-26 weeks duration and included 2,561 patients in total. In the meta-analysis, the weighted mean differences in change scores for cognition were in favor of EGb761 compared to placebo (-2.86, 95%CI -3.18; -2.54); the standardized mean differences in change scores for activities in daily living (ADLs) were also in favor of EGb761 compared to placebo (-0.36, 95%CI -0.44; -0.28); Peto OR showed a statistically significant difference from placebo for Clinicians' Global Impression of Change (CGIC) scale (1.88, 95%CI 1.54; 2.29). All these benefits are mainly associated with EGb761 at a dose of 240 mg/day. For subgroup analysis in patients with neuropsychiatric symptoms, 240 mg/day EGb761 improved cognitive function, ADLs, CGIC, and also neuropsychiatric symptoms with statistical superiority than for the whole group. For the Alzheimer's disease subgroup, the main outcomes were almost the same as the whole group of patients with no statistical superiority. Finally, safety data revealed no important safety concerns with EGb761. CONCLUSIONS: EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22-26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms.

Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis.

Despite B vitamin supplementation playing an important role in cognitive function, the exact effect remains unknown. The aim of this study was to systematically review and quantitatively synthesize the efficacy of treatment with vitamins B supplementation in slowing the rate of cognitive, behavioral, functional and global decline in individuals with MCI or AD. A systematic literature search in PubMed, EMBASE, International Pharmaceutical Abstracts, clinicaltrials. gov, the Cochrane Controlled Trials Register, the Cochrane Database of Systematic Reviews, and the Cochrane Cognitive Improvement Group specialized registry was conducted on April 2014, with no limit of date. Five trials met the eligibility criteria and were selected for this meta-analysis. Meta-analysis showed moderate beneficial effects of vitamins B supplementation on memory (SMD 0.60, 95% CI 0.20, 1.00), whereas no significant difference on general cognitive function (WMD -0.10, 95% CI -0.80, 0.59), executive function (SMD 0.05, 95% CI -0.11, 0.21) and attention (WMD -0.03, 95% CI -1.20, 1.14) were found in MCI patients. In addition, no significantly cognitive benefits on the Alzheimer's Disease Assessment Scale (ADAS-cog) (WMD 1.01, 95% CI -0.68, 2.70) and Mini Mental State Examination (MMSE) (WMD -0.22, 95% CI -1.00, 0.57), functional (SMD 0.13, 95% CI -0.05, 0.31), behavioral (SMD 0.04, 95% CI -0.16, 0.25) or global (WMD 0.07, 95% CI -0.48, 0.62) change were observed in AD patients. Collectively, weak evidence of benefits was observed for the domains of memory in patients with MCI. Nevertheless, future standard RCTs are still needed to determine whether it was still significant in larger populations. However, the data does not yet provide adequate evidence of an effect of vitamins B on general cognitive function, executive function and attention in people with MCI. Similarly, folic acid alone or vitamins B in combination are unable to stabilize or slow decline in cognition, function, behavior, and global change of AD patients.

Nutrition and the risk of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the major cause of dementia, and the increasing worldwide prevalence of AD is a major public health concern. Increasing epidemiological studies suggest that diet and nutrition might be important modifiable risk factors for AD. Dietary supplementation of antioxidants, B vitamins, polyphenols, and polyunsaturated fatty acids are beneficial to AD, and consumptions of fish, fruits, vegetables, coffee, and light-to-moderate alcohol reduce the risk of AD. However, many of the results from randomized controlled trials are contradictory to that of epidemiological studies. Dietary patterns summarizing an overall diet are gaining momentum in recent years. Adherence to a healthy diet, the Japanese diet, and the Mediterranean diet is associated with a lower risk of AD. This paper will focus on the evidence linking many nutrients, foods, and dietary patterns to AD.

Anticonvulsant effect of unilateral anterior thalamic high frequency electrical stimulation on amygdala-kindled seizures in rat.

Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. In this study, we examined the effect of unilateral high frequency stimulation (HFS) of the ANT on amygdala-kindled seizures in Wistar rats. When fully-kindled seizures were achieved by daily amygdala kindling, HFS (15 min train of 100 µs pulses at 200 Hz and 450-800 µA) was delivered to the ipsilateral or contralateral ANT immediately before the kindling stimulation for 15 days. HFS of the ipsilateral ANT significantly decreased the incidence of generalized seizures and the mean behavioral seizure stage and afterdischarge duration (ADD), and shortened cumulative ADD and cumulative generalized seizure duration. Furthermore, HFS of the ipsilateral ANT significantly increased the afterdischarge threshold (ADT). Our data suggest that unilateral HFS of the ANT may be an effective method of inhibiting kindled seizures by suppressing the susceptibility to seizures and generating long lasting anti-epileptic effect preventing the recurrence of kindled seizures, providing an alternative to bilateral ANT DBS for refractory epilepsy.

Low-frequency stimulation of bilateral anterior nucleus of thalamus inhibits amygdale-kindled seizures in rats.

Brain stimulation with low-frequency is emerging as an alternative treatment for refractory epilepsy. The anterior nucleus thalamus (ANT) is thought to be a key structure in the circuits of seizure generation and propagation. The present study aimed to investigate the effects of low frequency stimulation (LFS) targeting ANT on amygdala-kindled seizures in Sprague-Dawley rats. Electrodes were implanted into the right basolateral amygdala and the right or bilateral ANT of Sprague-Dawley rats. When fully kindled seizures were achieved by daily electrical stimulation of the amygdala, LFS (15 min train of 0.1 ms pulses at 1 Hz and 200-500 µA) was applied to the unilateral or bilateral ANT immediately before the kindling stimulation (pre-treatment). Our study showed that LFS of the bilateral ANT significantly decreased the incidence of generalized seizures (GS) and seizure stage, as well as shortened duration of afterdischarge and GS demonstrating an inhibition of the severity of seizures. Moreover, LFS elevated the afterdischarge threshold (ADT) and GS threshold indicating an inhibition of susceptibility to seizures. On the other hand, LFS of the unilateral ANT failed to show any significance in inhibiting seizures. Our study demonstrated that bilateral LFS in ANT could significantly inhibit amygdala-kindled seizures by preventing both afterdischarge generation and propagation. It provided further evidence for clinical use of LFS in ANT.