Volume 30, Supplement 2, June 2012 - "Metabolic-Cognitive Syndrome: Update on the Metabolic Pathway in Neurodegenerative Disorders" (Guest Editors: Vincenza Frisardi, Bruno Imbimbo)

Pages S1-S4
Vincenza Frisardi and Bruno Pietro Imbimbo
Introduction: Metabolic-Cognitive Syndrome: Metabolic Approach for the Management of Alzheimer’s Disease Risk

Pages S5-S13
Alexis M. Stranahan, Mark P. Mattson
Metabolic Reserve as a Determinant of Cognitive Aging
Abstract: Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) represent points on a continuum of cognitive performance in aged populations. Cognition may be impaired or preserved in the context of brain aging. One theory to account for memory maintenance in the context of extensive pathology involves ‘cognitive reserve,’ or the ability to compensate for neuropathology through greater recruitment of remaining neurons. In this review, we propose a complementary hypothesis of ‘metabolic reserve’, where a brain with high metabolic reserve is characterized by the presence of neuronal circuits that respond adaptively to perturbations in cellular and somatic energy metabolism and thereby protects against declining cognition. Lifestyle determinants of metabolic reserve, such as exercise, reduced caloric intake, and intake of specific dietary components can promote neuroprotection, while pathological states arising from sedentary lifestyles and excessive caloric intake contribute to neuronal endangerment. This bidirectional relationship between metabolism and cognition may be mediated by alterations in central insulin and neurotrophic factor signaling and glucose metabolism, with downstream consequences for accumulation of amyloid-β and hyperphosphorylated tau. The metabolic reserve hypothesis is supported by epidemiological findings and the spectrum of individual cognitive trajectories during aging, with additional data from animal models identifying potential mechanisms for this relationship. Identification of biomarkers for metabolic reserve could assist in generating a predictive model for the likelihood of cognitive decline with aging.

Pages S15-S30

Debomoy K. Lahiri, Bryan Maloney
The “LEARn” (Latent Early-life Associated Regulation) Model: An Epigenetic Pathway Linking Metabolic and Cognitive Disorders
Abstract: Diabetes, cardiovascular disease, hypertension, and other disorders have been unified within the metabolic syndrome. Recently, it has been proposed that Alzheimer’s disease (AD) and other degenerative, age-related neurological disorders may also be etiologically linked to the metabolic syndrome in a metabolic-cognitive syndrome. We review current evidence in the field for this unification. In addition, we describe how the latent early-life associated regulation (LEARn) model provides specific mechanisms to predict genetic targets for both metabolic disorders, e.g., diabetes, and neurodegenerative disorders, e.g., AD. The LEARn model is based on environmental induction of latent epigenetic misregulation, which develops into disease upon suffering additional environmental insults. We review structural differences between gene sequences that are and are not susceptible to LEARn misregulation. In addition to suggesting research targets such as the IDE and SORCS1 genes, which are implicated in both AD and diabetes, LEARn suggests specific mechanisms for pre-disease remediation, based on nutritional adjustment of aberrant DNA methylation and oxidation. The possibility of a single metabolic-cognitive disorder opens up the possibility of unified preventative treatments that reduce monetary and social costs of disease. LEARn suggests specific, testable pathways within the large theory.

Pages S31-S75

Francesco Panza, Vincenzo Solfrizzi, Giancarlo Logroscino, Stefania Maggi, Andrea Santamato, Davide Seripa, Alberto Pilotto
Current Epidemiological Approaches to the Metabolic-Cognitive Syndrome
Abstract: In the last decade, cumulative epidemiological evidence suggested that vascular- and metabolic-based risk factors may be important in the development of mild cognitive impairment and dementia. Epidemiological and basic research have also proposed a model of cognitive impairment linked to metabolic syndrome (MetS) and metabolic disorders, suggesting for research purposes a “metabolic-cognitive syndrome” (MCS) in patients with MetS plus cognitive impairment of degenerative or vascular origin. In particular, MetS has been associated with the risk of age-related cognitive decline and vascular dementia, but contrasting findings also existed on the possible role of MetS in overall dementia and Alzheimer’s disease. Among metabolic determinants of cognitive impairment, a better approach to the understanding of mechanisms could be to hypothesize a continuum leading to various degrees of late-life cognitive disorders in older subjects with metabolic-based risk factors. The MCS model could help us to explain the complex relationship between metabolic disorders and cognitive disturbances and the boundaries between normal and pathological conditions, with a better understanding of clinical and neuropathological features of these metabolic-based cognitive disorders. Strategies toward early and effective risk factor management could be of value in reducing the risk of MCS, so delaying the onset or preventing the progression of predementia syndromes. In the near future, clinical trials could be undertaken to determine if addressing MetS and metabolic-based risk factors, including inflammation, through lifestyle modification holds out the possibility of slowing down or ameliorating the cognitive aging process itself.

Pages S77-S87
Georgina E. Crichton, Merrill F. Elias, Jonathan Buckley, Karen J. Murphy, Janet Bryan, Vincenza Frisardi
Metabolic Syndrome, Cognitive Performance, and Dementia
Abstract: Obesity, hypertension, dyslipidemia, and insulin resistance have been associated with an increased risk of cognitive impairment or dementia. Together, these risk factors cluster as metabolic syndrome (MetS). The first aim of this systematic review was to identify and critically review studies assessing associations between MetS and cognition, with consideration given both to early cognitive changes and the severe endpoint of dementia. The second aim was to identify and discuss limitations in the literature and subsequent difficulties in drawing conclusions from research to date. Nine studies that assessed cognitive performance and ten studies that estimated incidence of dementia in relation to MetS were identified and appraised. Limitations in the literature include the lack of standardized nomenclature for cognitive variables, the use of multiple MetS definitions, and the difficulty in differentiating the adverse effects of multiple risk factors on cognition.

Pages S89-S95
Kelly Stanek Sellbom, John Gunstad
Cognitive Function and Decline in Obesity
Abstract: Obesity is a significant contemporary health concern that carries wide-ranging implications for society, as well as for individual health and well-being. In particular, the neuropsychological sequelae of obesity carry wide ranging functional implications. While research in this area is growing, our knowledge of obesity-related cognitive dysfunction and brain alterations has not yet been synthesized. The present review integrates the recent literature regarding patterns of obesity-related cognitive dysfunction and brain alterations and also indicates potential mechanisms for these neuropathological changes. The review culminates in a preliminary model of obesity-related cognitive dysfunction and suggestions for future research, including the potential reversibility of these changes with weight-loss.

Pages S97-S112
Deborah R. Gustafson
Adiposity and Cognitive Decline: Underlying Mechanisms
Abstract: 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.

Pages S113-S125
Merrill F Elias, Amanda L Goodell, Shari R Waldstein
Obesity, Cognitive Functioning and Dementia: Back to the Future
Abstract: The conditions of chronic obesity and overweight status are risk factors for lower cognitive performance, cognitive decline, cognitive deficit, and dementia. But lower cognitive performance early in life itself may be a risk factor for an increase in body weight over time. With this in mind, we review important papers in the literature that advance our knowledge of relations between weight and cognitive functioning, with an emphasis on papers that illustrate methodological and theoretical issues of importance. We describe the evolution in research on weight and cognition with respect to two major features: (a) the move backward in time from the diagnosis of dementia to the pre-clinical period of dementia in order to better identify risk factors; and (b) the evolution of studies from an earlier emphasis on obesity-related cardiovascular risk factors as major mediators of relations between obesity and cognition to a more recent emphasis on metabolic variables, lifestyle variables, genotype, and other mechanisms that explain relations among weight change, obesity, and cognition. We conclude that: 1) a complete understanding of the causal links between weight and cognitive functioning requires a lifespan perspective; 2) practically speaking, lifespan research may need to amalgamate and integrate research at different segments of the lifespan until such time that we can include the entire life cycle within a single study of weight and cognition; and 3) we need more studies that examine reciprocal relations between weight and cognition, especially early in life.

Pages S127-S145
Christiane Reitz
Dyslipidemia and Dementia: Current Epidemiology, Genetic Evidence, and Mechanisms Behind the Associations
Abstract: The role of cholesterol in the etiology of Alzheimer’s disease (AD) is still controversial. Some studies exploring the association between lipids and/or lipid lowering treatment and AD indicate a harmful effect of dyslipidemia and a beneficial effect of statin therapy on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E, apolipoprotein J, and the sortilin-related receptor.  Functional cell biology studies support a critical involvement of lipid raft cholesterol in the modulation of amyloid-β protein precursor (AβPP) processing by β- and γ-secretase resulting in altered amyloid-β production. Contradictory evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk. Additionally, cell biology studies suggest that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits co-localization of BACE1 and AβPP in non-raft membrane domains, thereby increasing generation of plasmin, an amyloid-β-degrading enzyme. The aim of this review is to summarize the findings of epidemiological and cell biological studies to elucidate the role of cholesterol in AD etiology.

Pages S147-S162
Peter van Vliet
Cholesterol and Late-Life Cognitive Decline
Abstract: High cholesterol levels are a major risk factor for cardiovascular disease, but their role in dementia and cognitive decline is less clear. This review highlights current knowledge on the role of cholesterol in late-life cognitive function, cognitive decline, and dementia. When measured in midlife, high cholesterol levels associate with an increased risk of late-life dementia and cognitive decline. However, when measured in late-life, high cholesterol levels show no association with cognitive function, or even show an inverse relation. Although statin treatment has been shown to associate with a lower risk of dementia and cognitive decline in observational studies, randomized controlled trials show no beneficial effect of statin treatment on late-life cognitive function. Lowering cholesterol levels may impair brain function, since cholesterol is essential for synapse formation and maturation and plays an important role in the regulation of signal transduction through its function as a component of the cell membrane. However, membrane cholesterol also plays a role in the formation and aggregation of amyloid-β. Factors that influence cholesterol metabolism, such as dietary intake, are shown to play a role in late-life cognitive function and the risk of dementia. In conclusion, cholesterol associates with late-life cognitive function, but the association is strongly age-dependent. There is no evidence that treatment with statins in late-life has a beneficial effect on cognitive function.

Pages S163-S178
Akhlaq A. Farooqui
Lipid Mediators and Their Metabolism in the Nucleous: Implications for Alzheimer’s Disease
Abstract: Lipid mediators are important endogenous regulators derived from enzymatic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. In neural cells, lipid mediators are associated with proliferation, differentiation, oxidative stress, inflammation, and apoptosis. A major group of lipid mediators, which originates from the enzymatic oxidation of arachidonic acid, is called eicosanoids (i.e., prostaglandins, leukotrienes, thromboxanes, and lipoxins). The corresponding lipid mediators of docosahexaenoic acid metabolism are named as docosanoids. They include resovins, protectins (neuroprotectins), and maresins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in brain tissue. Other glycerophospholipid-derived lipid mediators are platelet activating factor, lysophosphatidic acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators, such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine1-phosphate. These mediators are involved in differentiation, growth, cell migration, and apoptosis. Similarly, cholesterol-derived lipid mediators, hydroxycholesterol, produce apoptosis. Abnormal metabolism of lipid mediators may be closely associated with pathogenesis of Alzheimer’s disease.

Pages S179-S183
Research Report
Jonathan P. Little, Jocelyn M. Madeira, Andis Klegeris
The Saturated Fatty Acid Palmitate Induces Human Monocytic Cell Toxicity Toward Neuronal Cells: Exploring a Possible Link Between Obesity-Related Metabolic Impairments and Neuroinflammation
Abstract: Obesity is linked to increased risk of Alzheimer’s disease and cognitive impairment. Microglia-mediated neuroinflammation is implicated in neuronal loss. Elevated levels of fatty acids seen in obesity induce inflammation in peripheral tissues. Whether fatty acids promote neuroinflammation is unknown. Using an established neuroinflammation model involving human microglia-like THP-1 cells and SH-SY5Y neuroblastoma cells, we show that the saturated fatty acid palmitate, but not the unsaturated fatty acids oleate or linoleate, induces THP-1 cell pro-inflammatory cytokine secretion and neurotoxicity. Inhibition of c-Jun NH2-terminal kinase (JNK) reduces this neurotoxicity. Therefore, elevated saturated fatty acids may induce neuroinflammation through pathways involving JNK activation.

Pages S185-S198
José A. Luchsinger
Type 2 Diabetes and Cognitive Impairment: Linking Mechanisms
Abstract: This manuscript provides a brief review of current concepts in the mechanisms potentially linking type-2-diabetes (T2D) with cognitive impairment. Existing epidemiologic studies, imaging studies, autopsy studies, and clinical trials provide insights into the mechanisms linking T2D and cognitive impairment. There seems to be little dispute that T2D can cause cerebrovascular disease and thus cause vascular cognitive impairment (VCI). Whether T2D can cause late onset Alzheimer’s disease (LOAD) remains to be elucidated. Many epidemiologic studies show an association between T2D and cognitive impairment, but the association with VCI seems to be stronger compared to LOAD, suggesting that cerebrovascular disease may be the main mechanism linking T2D and cognitive impairment. Imaging studies show an association between T2D and imaging markers of LOAD, but these observations could still be explained by cerebrovascular mechanisms. Autopsy studies are few and conflicting, with some suggesting a predominantly cerebrovascular mechanism, and others providing support for a neurodegenerative mechanism. Thus far, the evidence from clinical trials is mixed in supporting a causal association between T2D and cognitive impairment, and most clinical trials that can answer this question are yet to be reported or finished. Given the epidemic of T2D in the world, it is important to elucidate whether the association between T2D and cognitive impairment, particularly LOAD, is causal, and if so, what are the mechanisms.

Pages S199-S215
Paula I. Moreira
Alzheimer’s Disease and Diabetes: An Integrative View of the Role of Mitochondria, Oxidative Stress, and Insulin
Abstract: An increasing number of studies have demonstrated a connection between Alzheimer’s disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies.

Pages S217-S229
Research Report
Suzanne M. de la Monte, Edward Re, Lisa Longato, Ming Tong
Dysfunctional Pro-Ceramide, ER Stress, and Insulin/IGF Signaling Networks with Progression of Alzheimer’s Disease
Abstract: In Alzheimer’s disease (AD), brain insulin and insulin-like growth factor (IGF) resistance and deficiency begin early, and worsen with severity of disease. The factors mediating progression of brain insulin/IGF resistance in AD are not well understood. We hypothesize that AD progression is mediated via negative cross-talk that promotes toxic ceramide generation and endoplasmic reticulum (ER) stress. The rationale is that insulin resistance dysregulates lipid metabolism and promotes ceramide accumulation, and thereby increases inflammation and stress. Consequences include disruption of cytoskeletal function and AβPP-Aβ secretion. The present study correlates AD stage with activation of pro-ceramide genes, ceramide levels, and molecular indices of ER stress in postmortem human brain tissue. The results demonstrated that in AD, brain insulin/IGF resistance was associated with constitutive activation of multiple pro-ceramide genes, increased ceramide levels, and increased expression of pro-ER stress pathway genes and proteins. Expression of several pro-ceramide and pro-apoptotic ER stress pathway molecules increased with AD severity and brain insulin/IGF resistance. In contrast, ER stress molecules that help maintain homeostasis with respect to unfolded protein responses were mainly upregulated in the intermediate rather than late stage of AD. These findings support our hypothesis that in AD, a triangulated mal-signaling network initiated by brain insulin/IGF resistance is propagated by the dysregulation of ceramide and ER stress homeostasis, which themselves promote insulin resistance. Therefore, once established, this reverberating loop must be targeted using multi-pronged approaches to disrupt the AD neurodegeneration cascade.

Pages S231-S249
Suzanne M. de la Monte
Triangulated Mal-signaling in Alzheimer’s Disease: Roles of Neurotoxic Ceramides, ER Stress, and Insulin Resistance Reviewed
Abstract: Ceramides are lipid signaling molecules that cause cytotoxicity and cell death mediated by insulin resistance, inflammation, and endoplasmic reticulum (ER) stress. However, insulin resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and ER stress. Herein, we discuss two major pathways, extrinsic and intrinsic, that converge and often overlap in propagating AD-type neurodegeneration via a triangulated mal-signaling network. First, we review evidence that systemic insulin resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues (e.g., liver) get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin resistance, inflammation, and cell death (extrinsic pathway). Then we discuss the role of the intrinsic pathway of neurodegeneration which is mediated by endogenous or primary brain insulin/IGF resistance, and impairs neuronal and oligodendrocyte survival, energy metabolism, membrane integrity, cytoskeletal function, and AβPP-Aβ secretion. The end result is increased ER stress and ceramide generation, which exacerbate brain insulin resistance, cell death, myelin degeneration, and neuroinflammation. Altogether, the data suggest that the triangulated mal-signaling network mediated by toxic ceramides, ER stress, and insulin resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.

Pages S251-S269
Patrick G Kehoe, Peter A Passmore
The Renin-Angiotensin System and Antihypertensive Drugs in Alzheimer’s Disease: Current Standing of the Angiotensin Hypothesis?
Abstract: There is an urgent need to improve upon Alzheimer’s disease (AD) treatments. Limitations of existing drugs are that they target specific downstream neurochemical abnormalities while the upstream underlying pathology continues unchecked. Preferable treatments would be those that can target a number of the broad range of molecular and cellular abnormalities that occur in AD such as amyloid-β (Aβ) and hyperphosphorylated tau-mediated damage, inflammation, and mitochondrial dysfunction, as well more systemic abnormalities such as brain atrophy, impaired cerebral blood flow (CBF), and cerebrovascular disease. Recent pre-clinical, epidemiological, and a limited number of clinical investigations have shown that prevention of the signaling of the multifunctional and potent vasoconstrictor angiotensin II (Ang II) may offer broad benefits in AD. In addition to helping to ameliorate co-morbid hypertension, these drugs also likely improve diminished CBF which is common in AD and can contribute to focal Aβ pathology. These drugs, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor antagonists (ARAs) may also help deteriorating cognitive function by preventing Ang II-mediated inhibition of acetylcholine release as well as interrupt the upregulation of deleterious inflammatory pathways that are widely recognized in AD. Given the current urgency to find better treatments for AD and the relatively immediate availability of drugs that are already widely prescribed for the treatment of hypertension, one of the largest modifiable risk factors for AD, this article reviews current knowledge as to the eligibility of ACE-inhibitors and ARAs for consideration in future clinical trials in AD.

Pages S268-S282
William V. Goodison, Vincenza Frisardi, Patrick G. Kehoe
Calcium Channel Blockers and Alzheimer’s Disease: Potential Relevance in Treatment Strategies of Metabolic Syndrome
Abstract: Midlife hypertension is a risk factor for late onset Alzheimer’s disease (AD) and it is one of the components of metabolic syndrome (MetS). Observational studies and some cardiovascular disease-related clinical trials suggest that antihypertensive treatment reduced the incidence and progression of AD. Calcium channel blockers (CCBs), one of the more commonly used treatments for hypertension, target voltage-gated calcium channels (VGCCs) which are found on neurons in the brain where calcium regulation is very important in both learning and memory. Amyloid-β (Aβ) peptide, one of the main pathological hallmarks of AD, causes increases to intracellular calcium via VGCCs, which in turn leads to further increases in Aβ production. Memantine, a current treatment used in AD, exerts some of its beneficial effects by blocking calcium entry into neurons. We explore the possibility of whether CCBs acting in the brain may delay the onset and progression of AD and thus may inform treatment regimes in people with MetS.

Pages S283-S304

Vincenza Frisardi
Apolipoprotein E Genotype: The Innocent Bystander or Active Bridge between Metabolic Syndrome and Cognitive Impairment?
Abstract: Apolipoprotein E [ApoE, APOE (gene)] is a multifunctional protein of the lipid and lipoprotein transport system mainly involved in metabolism of dietary lipids. Its polymorphic variants are considered a genetic risk factor of cognitive impairment in several neurodegenerative disorders such as Lewy body dementia, Huntington’s disease, and Alzheimer’s disease, as well as in vascular dementia and cerebrovascular disease. The precise mechanism by which APOE affects neurodegeneration is still unclear. Epidemiological and experimental studies demonstrated an influence of APOE on metabolic parameters but, to the best of our knowledge, no data are available about the exact role in humans of the effect of APOE on metabolic-cognitive syndrome (MCS). The latter is a model of cognitive impairment linked to metabolic syndrome identifying a grey zone between metabolic disorders and neuropathological process driving late-life cognitive decline. Although it may be a daring project that does not reach a final conclusion because of disease complexity, I hope to elucidate whether APOE may have a prominent role in MCS, going beyond the simple addition of separate mechanisms already known.