leptin and Dementia

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

Topics: Animals; Brain; Cognition Disorders; Dementia; Glucose; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Liver; Receptor, Insulin; Signal Transduction

Obesity is a pandemic and a serious global health concern. Obesity is a risk factor for multiple conditions and contributes to multi-morbidities, resulting in increased health costs and millions of deaths each year. Obesity has been associated with changes in brain structure, cognitive deficits, dementia and Alzheimer׳s disease. Adipokines, defined as hormones, cytokines and peptides secreted by adipose tissue, may have more widespread influence and functionality in the brain than previously thought. In this review, six adipokines, and their actions in the obese and non-obese conditions will be discussed. Included are: plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), tumor necrosis factors alpha (TNF-α), angiotensinogen (AGT), adiponectin and leptin. Their functionality in the periphery, their ability to cross the blood brain barrier (BBB) and their influence on dementia processes within the brain will be discussed.

Topics: Adipokines; Adiponectin; Angiotensinogen; Animals; Brain; Dementia; Humans; Interleukin-6; Leptin; Models, Biological; Obesity; Plasminogen Activator Inhibitor 1; Tumor Necrosis Factor-alpha

Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body.

Topics: Adiponectin; Adipose Tissue; Adiposity; Body Composition; Body Mass Index; Body Weight; Brain; Cognition Disorders; Cytokines; Dementia; Glucagon-Like Peptide 1; Humans; Leptin

Adipose tissue is an endocrine and paracrine organ that contributes to both metabolic and vascular homeostasis. Overweight and obesity due to excess adipose tissue, are cornerstones of vascular risk and increase risk for late-onset dementia. Vascular risk does not exist in isolation, and is accompanied by alterations in hormonal metabolism and metabolic syndromes. Thus, while vascular risk is highlighted as a primary mechanism for elevated dementia occurrence due to obesity, hormonal risk states may also precede or result from underlying dementia-related neuropathologies and direct neuronal toxicity. This is exemplified during the prodromal phase of dementia, as vascular and metabolic parameters decline in relation to dementia development, and potentially in a way that is different from 'normal' aging. In this review will be presented a review of the epidemiology of adiposity and dementia; adipose tissue biology; and two major hormones produced by adipose tissue, leptin and adiponectin, that interact directly with the brain. In addition, a synthesis related to other lines of supporting evidence for the role of adipose hormones in dementia will be provided. Understanding the role of adipose tissue in health of the brain is pivotal to a deeper understanding of dementia processes.

Topics: Adiponectin; Adipose Tissue; Adiposity; Dementia; Humans; Leptin; Risk Factors

Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Topics: Alzheimer Disease; Biomarkers; Brain Injuries; Brain Ischemia; Cerebrospinal Fluid Proteins; Cerebrospinal Fluid Rhinorrhea; Creutzfeldt-Jakob Syndrome; Dementia; Humans; Leptin; Low Back Pain; Moyamoya Disease; Multiple Sclerosis; Neurodegenerative Diseases; Nutrition Disorders; Paraneoplastic Cerebellar Degeneration; Parkinson Disease; Polymorphism, Genetic; Proteomics; Schizophrenia; Signal Transduction

Adipokines are hormones secreted by adipose tissue with roles in energy homeostasis and regulation of metabolism. Their dysregulation is suggested to contribute to the increased risk of dementia seen with midlife obesity, but longitudinal studies investigating this are scarce. We determined the association between plasma levels of adiponectin, leptin, and resistin with the risk of dementia.. We performed a case-cohort study embedded in the prospective, population-based Rotterdam Study. Plasma levels of the adiponectin, leptin, and resistin were measured at baseline (1997-1999) in a random subcohort of 945 participants without dementia, and additionally in 177 participants, who were diagnosed with dementia during follow-up (until January 1, 2018).. Higher levels of leptin and resistin were associated with a decreased risk of dementia (adjusted hazard ratio [95% confidence interval] per SD increase of log-transformed values: 0.85 [0.72-1.00] for leptin; 0.82 [0.71-0.95] for resistin). The association of leptin with dementia was further modified by body mass index and by APOE ε4 carrier status. Adiponectin levels were not associated with the risk of dementia.. These findings support the hypothesis that adipokines have a role in the pathophysiology of dementia. Future studies are warranted to confirm the findings and to explore the underlying mechanisms.

Topics: Adipokines; Adiponectin; Cohort Studies; Dementia; Humans; Leptin; Prospective Studies; Resistin

Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures.. We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence.. 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used.. Within 5 years of baseline, low BMI (<20 kg/m2) was associated with higher odds of dementia compared to those in the healthy BMI category (≥ 20-24.9 kg/m2). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05).. In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age ≥70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity.

Topics: Adiponectin; Adiposity; Aged; Aged, 80 and over; Anthropometry; Body Mass Index; Dementia; Fasting; Female; Humans; Independent Living; Leptin; Longitudinal Studies; Male; Psychiatric Status Rating Scales; Sex Factors; Sweden; Waist-Hip Ratio

animal studies suggest a neuroprotective role for leptin, but human studies have shown mixed results. We examined whether plasma leptin levels in individuals with mild cognitive impairment (MCI) were related to cognitive function at baseline and whether higher leptin levels were associated with reduced risk of dementia.. we categorised 352 MCI participants into sex-specific tertiles based on log-transformed fasting plasma leptin levels. In sex-stratified analyses, we investigated whether cognitive ability differed by leptin tertile. We also examined whether the risk of dementia over a 3-year follow-up period differed by leptin level. Analyses controlled for numerous potential confounding variables, including body mass index, hypertension and levels of blood insulin and C-reactive protein.. baseline cognitive ability did not differ as a function of leptin level, nor were higher leptin levels associated with reduced hazard of developing dementia. Controlling for related co-variates did not reveal any significant associations between leptin and dementia risk.. in this cohort of older adults with MCI, plasma leptin level was not associated with cognitive function at baseline, nor did it predict risk of dementia. Other biological measures, such as volumetric MRI and cerebrospinal fluid protein levels, have demonstrated robust dementia prediction in this cohort. Thus, the current negative findings suggest that plasma leptin, on its own, is unlikely to become a useful clinical biomarker for Alzheimer's disease. Efforts to develop other blood-based biomarkers are needed.

Topics: Aged; Aged, 80 and over; Biomarkers; Canada; Cognition; Cognitive Dysfunction; Comorbidity; Dementia; Female; Humans; Leptin; Male; Neuropsychological Tests; Predictive Value of Tests; Risk Factors; Time Factors; United States

Topics: Cognition; Cognitive Dysfunction; Dementia; Female; Humans; Leptin; Male

The association between obesity and dementia has been inconsistent, possibly due to changes in body composition often seen in old age. Leptin may be associated with better cognitive function. However, neuroprotection may be inhibited among obese subjects possibly due to leptin resistance. We sought to determine (i) if leptin is associated with risk of dementia or mild cognitive impairment (MCI) in a cohort of very old women, (ii) if this association is modified by obesity, and (iii) if leptin is a stronger risk factor compared with traditional anthropometric measures.. We studied 579 older women (mean age 82.6 years) from the ongoing prospective cohort Study of Osteoporotic Fractures, who were dementia-free at year-16 examination (our study baseline). Leptin (ng/mL) was measured using year-16 frozen serum, and anthropometric measures were collected during the same visit. Diagnosis of dementia/MCI was determined at year-20 examination.. There was evidence for a multiplicative interaction between log leptin and categorical body mass index (p = .03). Among women with body mass index <25kg/m(2) (n = 190), 1SD difference in log leptin (0.91ng/mL) was associated with 32% lower odds of dementia/MCI (OR = .68; 95% CI = .46, .99), after adjustment. The association was not significant among women with body mass index ≥25kg/m(2) (n = 377). Traditional anthropometric measures such as weight, height, and body mass index were not associated with dementia/MCI.. In this cohort of very old women, higher serum leptin was prospectively associated with lower odds of dementia/MCI in women with normal body mass index, but not in overweight or obese women. Leptin may be a better predictor of dementia/MCI than traditional anthropometric measures.

Topics: Aged; Aged, 80 and over; Aging; Biomarkers; Body Mass Index; Cognitive Dysfunction; Cohort Studies; Dementia; Female; Humans; Leptin; Obesity; Odds Ratio; Overweight; Prospective Studies; Risk Factors; United States

We have shown that high mid-life central adiposity may increase the risk for dementia after 32 years. Leptin, an adipose tissue hormone, is correlated with adiposity measures and may contribute to a better etiological understanding of the relationship between high adiposity and dementia. We explored the relationship between serum leptin in mid-life and dementia, which is a late-life outcome.. A longitudinal cohort study, the Prospective Population Study of Women, in Gothenburg, Sweden, includes a representative sample of 1462 women followed from mid-life ages of 38 to 60 years to late-life ages of 70 to 92 years. Women were examined in 1968, 1974, 1980, 1992, and 2000 using neuropsychiatric, anthropometric, clinical, and other measurements. Serum leptin was measured on samples collected at the 1968 baseline examination, after storage at -20°C for 29 years. Cox proportional hazards regression models estimated incident dementia risk by baseline leptin. Logistic regression models related leptin levels to dementia among surviving participants 32 years later. All models were adjusted for multiple potential confounders.. Mid-life leptin was not related to dementia risk using Cox or logistic regression models. This was observed despite positive baseline correlations between leptin and adiposity measures, and given our previous report of high mid-life waist-to-hip ratio being related to a twofold higher dementia risk.. Leptin is not a mid-life marker of late-life dementia risk in this population sample of Swedish women born between 1908 and 1930.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anthropometry; Cohort Studies; Community Health Planning; Dementia; Fasting; Female; Humans; Leptin; Life Style; Middle Aged; Psychiatric Status Rating Scales; Sweden

Topics: Animals; Antidepressive Agents; Appetite Depressants; Blood-Brain Barrier; Dementia; Depression; Humans; Leptin; Nootropic Agents; Obesity

Topics: Aged; Alzheimer Disease; C-Reactive Protein; Dementia; Humans; Leptin; Middle Aged; Obesity; Risk

The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD).. To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors.. Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed.. Incidence of dementia and AD during follow-up until December 31, 2007.. During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance.. Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Dementia; Female; Follow-Up Studies; Humans; Leptin; Magnetic Resonance Imaging; Male; Prospective Studies

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Comorbidity; Cost of Illness; Dementia; Enzyme Inhibitors; Flurbiprofen; Global Health; Humans; Leptin; Longevity; Peptide Fragments

Leptin is a peptide hormone secreted by adipocytes. It has been shown to modulate production and clearance of amyloid beta (Abeta) in rodent models. We sought to determine if serum leptin was associated with cognitive decline in the elderly. We studied 2871 well-functioning elders, aged 70-79, who were enrolled in a prospective study. Serum leptin concentrations were measured at baseline and analyzed by mean+/-1S.D. Clinically significantly cognitive decline over 4 years was defined as > or =5-point drop on the Modified Mini Mental State Exam (3MS). Compared to those in the lower leptin groups, elders in the high leptin group had less cognitive decline, 20.5% versus 24.7% (OR=0.79; 95% CI 0.61-1.02, p=0.07). After adjustment for demographic and clinical variables, including body mass index and total percent body fat, those in the high leptin group had significantly less likelihood of cognitive decline, OR=0.66 (95% CI 0.48-0.91). We conclude that in elderly individuals, higher serum leptin appears to protect against cognitive decline, independent of comorbidites and body fat.

Topics: Adipose Tissue; Aged; Aging; Biomarkers; Body Mass Index; Cognition Disorders; Dementia; Disease Progression; Humans; Leptin; Metabolic Syndrome; Neuropsychological Tests; Obesity; Prospective Studies

Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Female; Humans; Hyperphagia; Leptin; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Reference Values; Sex Factors