Metabolic A and Alzheimer Disease

Ageing Research Reviews 9 (2010) 399417
Contents lists available at ScienceDirect
Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr
Review
Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimers disease

Vincenza Frisardi a, , Vincenzo Solfrizzi a , Davide Seripa b , Cristiano Capurso c , Andrea Santamato d , Daniele Sancarlo b , Gianluigi Vendemiale c , Alberto Pilotto b , Francesco Panza b,
a
Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Policlinico, Piazza Giulio Cesare, 11, 70124, Bari, Italy Geriatric Unit and Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Foggia, Italy Department of Geriatrics, University of Foggia, Foggia, Italy d Department of Physical Medicine and Rehabilitation-OORR Hospital, University of Foggia, Italy
b c
a r t i c l e
i n f o
a b s t r a c t
A growing body of epidemiological evidence suggested that metabolic syndrome (MetS) and Mets components (impaired glucose tolerance, abdominal or central obesity, hypertension, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol) may be important in the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), vascular dementia, and Alzheimers disease (AD). These suggestions proposed in these patients the presence of a metabolic-cognitive syndrome, i.e. a MetS plus cognitive impairment of degenerative or vascular origin. This could represent a pathophysiological model in which to study in depth the mechanisms linking MetS and MetS components with dementia, particularly AD, and predementia syndromes (ARCD or MCI), suggesting a possible integrating view of the MetS components and their inuence on cognitive decline. In the present article, we discussed the role of these factors in the development of cognitive decline and dementia, including underlying mechanisms, supporting their inuence on -amyloid peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD. In the next future, trials could then be undertaken to determine if modications of these MetS components including inammation, another factor probably related to MetS, could lower risk of developing cognitive decline. Future research aimed at identifying mechanisms that underlie comorbid associations of MetS components will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing cognitive disorders. 2010 Elsevier B.V. All rights reserved.
Article history: Received 21 April 2010 Accepted 23 April 2010
Keywords: Metabolic syndrome Alzheimers disease Mild cognitive impairment Leptin Insulin resistance Hypertension
1. Introduction With global increases in population size and life expectancy, Alzheimers disease (AD) has become a world health problem. According to future previsions, the global prevalence of AD is set to rise to more than 35 million people by 2010. Moreover, the dementia prevalence will nearly double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050 (Ferri et al., 2005). To date, current treatment options for AD only address symptoms, and no treatments are available to prevent or delay the disease process (Panza et al., 2009a). From a neuropathological view, AD involves aberrant protein processing and is characterized by the presence of both intra-neuronal protein clusters composed of paired helical laments of hyperphosphorilated tau protein [neurobrillary tan-
Corresponding author. Corresponding author. Tel.: +39 0882 416 260; fax: +39 0882 416 264. E-mail addresses: vfrisardi@yahoo.com (V. Frisardi), geriat.dot@geriatria.uniba.it (F. Panza). 1568-1637/$ see front matter 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.arr.2010.04.007
gles (NFTs)], and extracellular aggregates of -amyloid (A ) [Senile Plaques (SPs)] which molecular pathway discovery has allowed to see positively towards disease-modifying therapy (Frisardi et al., 2010a). Several risk factors have been identied for late onset AD classied into genetic and non genetic. Since less than 5% of cases of AD is traceable to genetic causes, identication, management, and mechanisms understanding that link other risk factor to neuropathological process, is mandatory to decrease the burden of AD. Epidemiological research supported the hypothesis that modiable vascular and lifestyle-related factors were associated to the development of dementia and predementia syndromes in late life and this studies have identied multiple potentially preventable risk factors (Solfrizzi et al., 2004; Panza et al., 2008; Peters, 2009). In particular, the vascular and related factors that have been associated with dementia and cognitive decline included high blood pressure (BP) and hypertension, total cholesterol and other lipid parameters, diabetes and insulin resistance, body mass index (BMI) and obesity, and the metabolic syndrome (MetS) (Panza et al., 2004; Solfrizzi et al., 2008). Furthermore, the lifestyle-related factors, such as physical activity, diet, and nutrition are deter-
400
V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417
minants of successful aging. A healthy diet habit is increasingly recognized as adherence to a Mediterranean-type diet that was ssociated with decreased cognitive decline maybe for its impact on many of the possible risk factors detailed above, and on possible disease-modifying treatments (Peters, 2009; Frisardi et al., 2010b). In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI) (Solfrizzi et al., 2010a), while sh consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) intake were associated to reduced risk of cognitive decline and dementia (Solfrizzi et al., 2010a,b). Furthemore, light to moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for vascular dementia (VaD), cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect (Panza et al., 2009b). Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Smoking is known to increase cardiovascular risk and has been linked to the development of dementia (Anstey et al., 2007). Despite early studies suggesting that nicotine itself may impact positively upon cognitive function smoking clearly does not and in fact doubt is now being cast upon the longterm effects of nicotine use also (Swan and Lessov-Schlaggar, 2007). Interestingly, an important exercises regulating role on several molecular pathway involving in the changes in brain function as well as central insulin-like growth factor-1 (IGF-1), monoamines, Wnt signaling, glucocorticoids, mitochondrial stress proteins, and the nitric oxide (NO) pathway was suggested (Stranahan et al., 2009). Consequently, physical exercise appeared to have clear protective effects on cognitive functioning and possible reduction in incident dementia (Colcombe et al., 2003; Solfrizzi et al., 2008). For the latter, whether this is due to education or socio-economic status per se or related to lifetime occupation and or level of cognitive exercise is debated (Ngandu et al., 2007; Solfrizzi et al., 2008; Peters, 2009). Evidence of overlap between degenerative and vascular disorders is emerging from pathologic and epidemiological studies. In older subjects, particularly over age 85 years, the prevalence of vascular factors and other medical conditions that impair cognition increases substantially. MetS, is a multifactorial disorder represented by the co-occurrence of several vascular conditions related to central obesity that also includes impaired glucose metabolism, dyslipidemia, and high BP and that depicts a risk status for both type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) (Panza et al., 2008). Traditionally, vascular risk factors taken separately such as hypertension, dyslipidemia, and diabetes have been demonstred to play an important role in the development of MCI, dementia, and AD. Some investigators have suggested that inammation should be added as a component in the denition of MetS because it is such an important part of the pathophysiology (Haffner, 2006). In most studies, MetS is dened using the Third Adults Treatment Panel of the National Cholesterol Education Program (NCEP-ATP-III) criteria whereas, the subjects with MetS were identied by any combination of three or more of the following components: abdominal or central obesity (waist circumference >102 cm for men and >88 cm for women); elevated plasma triglycerides (TGs) (150 mg/dl); low high-density lipoprotein (HDL) cholesterol (<40 mg/dl for men and <50 mg/dl for women); high BP (130/85 mm Hg) or being in hypertensive treatment; high fasting plasma glucose (110 mg/dl) or being in oral antidiabetic treatment (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001). However, at least other two more recent set of clinical criteria were also diffused, the National Heart, Lung and Blood Institute/American Heart Association (NHLBI/AHA) criteria (Grundy et
al., 2005) and the International Diabetes Federation (IDF) criteria (Alberti et al., 2005), with slight differences in the operational definitions. 1.1. Metabolic syndrome, dementia, and cognitive decline From an epidemiological point of view, MetS appeared to increase the risk for ARCD (Yaffe et al., 2004a, 2007; Dik et al., 2007; Komulainen et al., 2007; van den Berg et al., 2007; Ho et al., 2008), while for MCI and its progression to dementia the ndings were too limited to draw any conclusion (Yaffe et al., 2009; Solfrizzi et al., 2009; Roberts et al., 2010). In fact, a very recent study found an association between MetS and the number of its components and risk of developing cognitive impairment (clinically adjudicated dementia or MCI or cognitive impairment not clinically adjudicated) on older women with osteoporosis from clinical centers (Yaffe et al., 2009). In a large longitudinal Italian population-based sample with a 3.5-year follow-up, in a total of 2097 participants from a sample of 5632 6584 year-old subjects from the Italian Longitudinal Study on Aging, among MCI patients those with MetS had a higher risk of progression to dementia compared with those without MetS (Solfrizzi et al., 2009). Furthermore, several studies suggested that MetS may be linked to the risk of developing dementia and VaD (Kalmijn et al., 2000; Roriz-Cruz et al., 2007; Raffaitin et al., 2009; Solfrizzi et al., 2010b). On the contrary, contrasting ndings existed of the possible role of MetS in developing AD in both population-based and casecontrol studies (Vanhanen et al., 2006; Razay et al., 2007; Muller et al., 2007; Raffaitin et al., 2009; Solfrizzi et al., 2010b). Several individual components of MetS have been linked to risk of developing dementia and cognitive impairment. Among the ve MetS components, hyperglycemia, lower HDL levels, and elevated triglyceride levels were the components with increased risk for predementia syndromes. Furthermore, hypertriglyceridemia was the component with increased risk of dementia syndromes, particularly VaD (Raffaitin et al., 2009; Solfrizzi et al., 2010b). It is difcult to establish mechanistic links between individual risk factors and dementia especially in presence of the metabolic syndrome whereas multiple vascular risk factors interplay a complex role in the pathogenesis of dementing disorders than just one. Usually, the components of MetS have been considered into independent manner from a pathophysiological point of view, almost as if MetS are a sum of different disorders and neuronal damage are the nal center where all components effects converge but this view will be reductive to explain the metabolic global effects on cognitive decline. A better approach to mechanism understanding could be to see among metabolic alterations a continuum that leading to various degree of cognitive disorders (Luchsinger and Gustafson, 2009), and formulating hypothesis on a metabolic-cognitive syndrome (MCS) to explain the complex relationship between metabolic disorders and cognitive disturbances and the boundaries between normal and pathological condition (Frisardi et al., 2010c). These suggestions permitted to hypothesize the presence of a MCS in patients with MetS plus cognitive impairment of degenerative or vascular origin that could help us to better understand neuropsychological and neuropathological features of these predementia or dementia syndromes present in MetS. The identication of a clinical prole of the MCS could be central in detecting in these patients also a molecular prole of higher risk to develop predementia or dementia syndrome, as happened for MetS and T2DM or CAD. Therefore, the MCS is not a clinical label but rather a pathophysiological model. In the present review article, we discussed in depth the mechanisms linking MetS with dementia (particularly AD) and predementia syndromes (ARCD or MCI), suggesting a possible integrating view of the MetS components and their inuence on cognitive decline. Special attention was paid to the possible role
401
of MetS components, i.e., adiposity and/or abdominal/central obesity, impaired glucose tolerance and/or T2DM, hypertension and/or elevated BP, hypertriglyceridemia, and reduced HDL cholesterol, in predementia and dementia syndromes.
nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival (Meloni et al., 2010), which are both desirable for postinfarction myocardial healing other that to elicite pleiotropic benecial actions on hepatic myobroblast survival (Kendall et al., 2009). 2.1. Adiposity and cognitive decline: underlying mechanisms Adiposity refers to the amount of adipose tissue in the body (Luchsinger and Gustafson, 2009). Adiposity is a continuum, and the normal or ideal threshold of adiposity is not clear, but its increasing is associated with higher risk of other MetS components, such as insulin resistance, T2DM, hypertension, and dyslipidemia (Pi-Sunyer, 2002). Adiposity is usually measured indirectly with anthropological measures (Mueller et al., 1991) such as the BMI (kg/m2 ), that is strongly correlated with total body fat tissue and a good indirect measure of adiposity (Pi-Sunyer, 2002), although this correlation decreases in older age (Baumgartner et al., 1995). Another commonly used measure of adiposity is waist circumference, that is meant to measure the accumulation of adipose tissue in the abdomen (abdominal/central obesity), the largest depot of adipose tissue, and thus, perhaps it is a more direct measure of adiposity compared to BMI (Mueller et al., 1991). Elevated waist circumference is also related to a higher risk of T2DM, hypertension, dyslipidemia, and heart disease, and some studies have shown that it is a better predictor of adverse cardiovascular outcomes compared to BMI (Janssen et al., 2004), and some have advocated its use as the best measure of adiposity (Mueller et al., 1991). A commonly used cutoff to dene elevated waist circumference is 102 cm for men and 88 cm for women (Janssen et al., 2004). Both high (>29), low (<21), rising and falling BMI have been associated with increased risk of cognitive decline, possibly via an ongoing disease process and or poor nutrition related to lower levels, and an increased cardiovascular risk at higher levels (Panza et al., in press). Weight loss seems to occur during the preclinical phases of dementia, and recent follow-up studies have suggested that low BMI could actually be an early sign of dementia (Nourhashmi et al., 2003; Stewart et al., 2005) (Table 1). Interestingly, in a 20-year prospective study of 299 community-dwelling older adults, it was found that weight loss precedes mild and moderate dementia, suggesting that early weight loss is unlikely to be a consequence of AD itself, and that AD may be linked to underlying metabolic abnormalities (Barrett-Connor et al., 1998). In the past, studies reported that a low BMI was a risk factor for dementia (White et al., 1996). However, these observations were based on cross-sectional studies, and with dementia previously obese patients may lose up to 50% of their predementia body weight (Wang, 2002). Epidemiological studies of increased BMI as a risk factor for dementia have shown conicting results (Gustafson, 2006; Gorospe and Dave, 2007; Luchsinger et al., 2007a; Luchsinger and Gustafson, 2009; Fitzpatrick et al., 2009) (Table 1). Nevertheless, the studies with statistically signicant results had larger sample sizes, longer follow-up periods, and younger participants at baseline (Gorospe and Dave, 2007). In fact, elevated BMI in middle age may be associated with higher dementia risk (Gustafson et al., 2003; Kivipelto et al., 2005; Whitmer et al., 2005, 2008) (Table 1). Adipose tissue is not only a storage of fat but is also the largest endocrine organ in the human body secreting hormones, cytokines, and growth factors (Gustafson, 2006). To date, amount to more than 50 different molecular entities are discovered generally referred to as adipokines that appear involved in a wide range of physiological processes as haemostasis [e.g., plasminogen activator inhibitor-1 (PAI-1)], lipid metabolism [e.g., cholesteryl ester transfer protein and apolipoprotein E (APOE)], BP regulation (angiotensinogen), insulin sensitivity (e.g., adiponectin, resistin and visfatin) and angiogenesis [e.g., vascular endothelial growth
2. Pathogenetic associations between metabolic syndrome components and Alzheimers disease Genetic, environmental, and lifestyle factors all together are responsible in rst line of predisposition for the development of metabolic disease as well as neurodegenerative disorders. Nutritional signaling integrated by cerebral structures in particular hypothalamus, activates a chain of neurochemical events and triggers relationship between brain functions and metabolism. In fact, a contributor to brain alterations in MetS could be a dysregulation of the hypothalamicpituitaryadrenal (HPA) axis, as stress-compatible circulating levels of corticosterone, associated with a down-regulation of glucocorticoid receptor in the hippocampus, a region particularly vulnerable in AD, have been found in T2DM rats (Beauquis et al., 2010) (Table 2). Glucocorticoids elicit insulin resistance in the hippocampus and many pathophysiological conditions are associated with HPA axis dysregulation, including aging, affective disorders, and metabolic diseases, particularly T2DM. Although there are divergent criteria for the identication of the MetS, they all tend to agree that the driving force of MetS is the abdominal adiposity or central obesity (Cornier et al., 2008). When the storage capacity of adipose tissue is exceeded, then a continuous exposure to fatty acids by food intake, not balanced with by increased fatty acid oxidation, will lead to deposition of fatty acids as triglycerides in ectopic sites, such as liver, skeletal muscle, heart muscles, pancreatic islets, and the peri-vascular tissue; generally, it is assumed that this ectopic fat accumulation is implicated in the metabolic dysfunction (Rasouli et al., 2007). In fact not all overweight or obese individuals are metabolically unhealth because the human body is biologically programmed to maintain internal homeostasis through negative feedback-regulatory mechanisms. The term allostasis is conied to represent more completely the bodys ability of response to threats in an anticipatory fashion in order to keep the internal milieu stable involving several systems and not only one feedback loop mechanism. Information regarding (potentially) dangerous situations or threats in the environment is processed in limbic brain structures (including the hippocampus, the amygdala and the prefrontal cortex) opening a set of regulatory responses whether hormonal or metabolic (van Dijk and Buwalda, 2008). The damage that the allostatic response causes when stressors are inescapable is termed allostatic load, and this resembles, in fact, many aspects of the metabolic syndrome (Korte et al., 2005; McEwen, 2000). Consequently, the MetS may be a maladaptive consequence of an initially adaptive strategy to deal with environmental demands, suggesting a potential link between brain action/dysfunction and metabolic disorders. Several hormones and peptides produced into organs outside cerebral nervous system (CNS) show your effects in the brain crossing blood barrier brain (BBB) and vice-versa in a particular molecular cross-talk between CNS and peripheral organs (van Dijk and Buwalda, 2008) In fact, insulin, leptin, cortisol, estrogens were demonstred to act inuencing the cognitive functions, while other neuropeptides appeared to play a role in various distinct functions such as orexin that intervenes regulating gastric secretion and gastrointestinal motility (Baccari, 2010) or adrenocorticotropin (ACTH), one of several peptide hormones derived from proopiomelanocortin (POMC), and processed and secreted from the pituitary to stimulate cortisol production from the adrenal gland and further it seems to have effects on bone metabolism in vivo. (Isales et al., 2010). Moreover,
402
Table 1 Principal longitudinal population-based studies on the relationships among the components of metabolic syndrome (MetS) [abdominal obesity and/or body mass index (BMI), impaired glucose tolerance (IGT) and/or type 2 diabetes mellitus (T2DM), hypertension and/or elevated blood pressure] and cognitive impairment, age-related cognitive decline, mild cognitive impairment (MCI), dementia, vascular dementia (VaD), and Alzheimers disease (AD) in older subjects. MetS components Reference Setting and study design Subjects Assessment of cognition or diagnosis of dementia Incident diagnosis of dementia Principal ndings
Abdominal obesity or BMI Nourhashmi et al. (2003) The Personnes Ages Quid (PAQUID) Study France
Longitudinal, population-based (8 years)
3646 individuals aged 65 years or older
Subjects with a BMI <21 had an increased risk of developing dementia as compared with subjects whose BMI was between 23 and 26. However, when individuals who developed dementia early during the follow-up were excluded from the analysis, this relationship was no longer signicant Dementia-associated weight loss begins before the onset of the clinical syndrome and accelerates by the time of diagnosis V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417 Obesity at midlife is associated with an increased risk of dementia and AD later in life. Clustering of vascular risk factors increases the risk in an additive manner A high BMI had a signicant higher risk of dementia after adjusting with vascular comorbidities and socioeconomic status Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities
Stewart et al. (2005) The Honolulu-Asia Aging Study (HAAS) USA Kivipelto et al. (2005) The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study Finland Whitmer et al. (2005) The Kaiser Permanente Medical Care Programme USA Whitmer et al. (2008) The Kaiser Permanente Medical Care Programme USA Gustafson et al. (2003) The Gteborg Study Sweden Luchsinger et al. (2007a,b) The Washington Heights-Inwood Columbia Aging Project USA Fitzpatrick et al. (2009) The Cardiovascular Health Cognition Study USA IGT or T2DM Yaffe et al. (2004) The Multiple Outcomes of Raloxifene Evaluation (MORE) dementia ancillary study USA
1890 men (aged 7798 years)
Incident diagnosis of dementia
1449 individuals aged 6579 years
Incident diagnosis of dementia and AD
10,276 subjects, mean age: 74.5 years
6583 subjects, 7387 years of age
392 nondemented adults who were followed up from age 70 to 88 years 1484 subjects, 65 years and older
For every 1.0 increase in BMI at 70 years old, AD risk increased by 36% after adjusting with vascular confounding factors In younger elderly (6576 years of age), the association between BMI quartiles and AD resembles a U shaped-curve, while in the oldest old (>76 years) higher BMI is related to a lower AD risk Elevated self-reported BMI at age 50 years was associated with a higher risk of dementia, while BMI at age 65 or older in the same individuals did not
Longitudinal, population-based (5.4 years)
2798 adults without dementia (mean age:74.7 years)
Incident diagnosis of dementia, AD, and VaD
7027 osteoporotic postmenopausal women (mean age, 66.3 years)
The main outcome was baseline and 4-year change on ve standardized cognitive tests (z scores with lower scores indicating worse performance) and risk of developing clinically signicant impairment (dementia, MCI, or very low cognitive score)
Diabetic as well as pre-diabetic women have impaired cognitive performance and greater risk of developing cognitive impairment
Kanaya et al. (2004) The Rancho Bernardo Study USA Grodstein et al. (2001) Nurses Health Study USA
999 white men and women aged 4289 years
Three cognitive tests (MMSE, VF test, and TMT-B) were measured
Elderly white women with diabetes had a more rapid decline in performance on the VF test compared with women with IGT or normal glucose tolerance T2DM was related to lower scores on several aspects of cognitive function. Longer duration of T2DM may be associated with poorer scores, but hypoglycemic therapy may ameliorate cognitive scores T2DM is associated with lower levels of cognitive function and greater cognitive decline among older women V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417
Cross-sectional, population-based
2374 participants (7078 years of age)
Four tests of cognitive function (TICS, immediate and delayed recall of the EBMT, and VF) by telephone
Gregg et al. (2000) Study of Osteoporotic Fractures Research Group USA
Community-dwelling white women 65 years and older (n = 9679)
Three tests of cognitive function, the DST, the TMT-B, and a modied version of the MMSE (3MS), were administered at baseline and 36 years later The neuropsychological test battery included the BSRT, the Russells adaptation of the VRT, the TMT, the VF test for letters and category, and the MMSE Their cognitive abilities were assessed at baseline by the MMSE and eight domain-specic tests, and they were reassessed 4 years later Cognitive test measures were the MMSE, WAIS-Revised Digits Forward, FOME, clock drawing, and two Color TMT
Vanhanen et al. (1998) The Kuopio Study Finland
1300 older subjects, (mean age: 73.2 years)
Persistent IGT in the elderly was associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association Despite similar high initial cognitive function, diabetic subjects tended to have an unfavorable evolution of cognitive performance over 4 years compared with subjects who had normal glucose or IGT No increased risk for cognitive impairment in participants with diabetes compared with those with normal glucose tolerance was found after adjustments for ethnicity, sex, age, education, and presence of depression, before or after elimination of dementia T2DM was related to a higher risk of CIND with stroke (vascular CIND), although the effect on CIND without stroke was not evident after adjusting for demographic variables and the presence of the APOE 4 allele T2DM was related only to vascular CIND
Fontbonne et al. (2001) The Epidemiology of Vascular Aging (EVA) Study France Lindeman et al. (2001) The New Mexico Elder Health Survey USA
1389 older subjects, aged 5971 years
Cross-sectional, population-based
Elderly Hispanic individuals (n = 414) and non-Hispanic white individuals (n = 469) aged > or = 65 years
Luchsinger et al. (2001) The Washington Heights-Inwood Columbia Aging Project USA
1262 elderly subjects without dementia (mean age: 76.5 years)
Incident AD and dementia associated with stroke
MacKnight et al. (2002) The Canadian Study of Health and Aging Canada Luchsinger et al. (2007b) The Washington Heights-Inwood Columbia Aging Project USA
5574 older subjects, aged 65 years and older
Incident dementia (including AD and vascular cognitive impairment)
918 subjects, aged 65 years and older
Incident all-cause MCI, aMCI, and naMCI
T2DM was related to a higher risk of both aMCI and naMCI, underlining the importance of T2DM for both AD related and vascular cognitive impairment
403
404
Table 1 (continued ) MetS components Reference Curb et al. (1999) The Honolulu-Asia Aging Study (HAAS) USA Ott et al. (1999) [112] The Rotterdam Study The Netherlands Leibson et al., 1997 [114] The Rochester Epidemiology Project USA Xu et al. (2004) The Kungsholmen Project Study Sweden Setting and study design Longitudinal, population-based (26 years) Subjects 3774 participants, who were examined at ages 4568 years and again at ages 7193 years Assessment of cognition or diagnosis of dementia Incident diagnosis of dementia, AD, and VaD Principal ndings No association between AD and diabetes, present either 25 or 15 years previously, was found. A signicant association was found between IGT at baseline and VaD T2DM almost doubled the risk of dementia and AD
6370 subjects, aged 65 years and older
A cohort of 1455 persons with T2DM, aged 5971 years
Persons with T2DM exhibited signicantly increased risk of all dementia. Risk of AD was also elevated
1301 community dwellers aged 75 years and older
Diabetes mellitus increases the risk of dementia, and VaD in particular, in very old people. The risk for dementia and VaD is especially high when diabetes mellitus occurs together with severe systolic hypertension or heart disease The risk of AD increased with the number of vascular risk factors, diabetes mellitus, hypertension, heart disease, and current smoking. Different combinations of risk factors were associated with a high risk of AD. Diabetes mellitus and smoking were the strongest risk factors An increased risk of cognitive decline at higher levels of BP. For every 10 mm Hg increase in systolic BP, this study found a 7% increased risk of intermediate cognitive function (a score between 82 and <92 on the CASI) and a 9% increased risk of poor cognition (a CASI score of <82) Systolic and diastolic BPs were both inversely related to cognitive function. For every 1 mm Hg rise in diastolic BP, a composite neuropsychological score decreased by 0.068 of a standard score unit
Luchsinger et al. (2005) The Epidemiology of Vascular Aging (EVA) Study USA
1138 individuals without dementia at baseline (mean age = 76.2 years)
Incident diagnosis of possible and probable AD
Hypertension and elevated blood pressure Launer et al. (1995) The Honolulu-Asia Aging Study (HAAS) USA
3735 participants, with an average age of 78 years
Cognitive abilities assessed with the CASI
Elias et al. (1993) The Framingham Heart Study USA
1702 participants aged 5588 years
Cognitive abilities were assessed with sub-tests of WAIS, WMS, and MAE: Logical Memory-immediate and delayed recall, Visual Reproductions, Paired Associate Learning, Number of Digits-forward and backward, Word Fluency, and Similarities. Cognitive decline dened as a drop in the MMSE score of four points during the assessment period Diagnosis of MCI
Tzourio et al. (1999) The Epidemiology of Vascular Aging (EVA) Study France DeCarli et al., 2001 The National Heart, Lung, and Blood Institute Twin Study USA
1373 individuals of 5971 years of age
Higher BP at baseline was related to higher rates of cognitive decline
369 individual twins, aged 6781 years
Midlife diastolic BP increased the risk for MCI but only when a history of symptomatic CVD was excluded
Solfrizzi et al., 2004 The Italian Longitudinal Aging Study (ILSA) Italy Tervo et al. (2004) The Kuopio Study Finland Reitz et al. (2007) The Washington Heights-Inwood Columbia Aging Project USA Skoog et al. (1996) The Longitudinal Population Study of 70-year-olds Sweden
Diagnosis of MCI
Hypertension was related to a 44% higher risk of MCI related to diabetes that was close to statistical signicance, but no distinction was made between persons with aMCI or naMCI This study also found that hypertension was related to a higher risk of MCI, without distinction of MCI subtype Higher BP at baseline was related to higher rates of cognitive decline V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417
Diagnosis of MCI
918 participants (aged 65 years and older)
Diagnosis of MCI, aMCI, and naMCI
Diagnosis of dementia, AD, and VaD
High BP even later in life and closer to dementia onset has also been linked with a higher AD risk, but results are more inconsistent. In fact, this 15-year longitudinal study reported increased blood pressure 1015 years before the onset of both AD and VaD A high systolic BP in midlife was related to later development of AD
Kivipelto et al. (2002) The North Karelia Project and the FINMONICA Finland Qiu et al., 2003 The Kungsholmen Project Sweden
1449 participants, aged 6579 years
Diagnosis of dementia, and AD
Systolic BP greater than 180 mm Hg was associated with a signicant adjusted relative risk for incident AD. Lower systolic BP (140 mm Hg) was not related to incident dementia. In contrast, high diastolic BP (>90 mm Hg) was not associated with dementia incidence, whereas extremely low diastolic pressure (</=65 vs. 6690 mm Hg) produced a relative risk for AD and for dementia Over a 32-year period, compared with men who did not, those who did develop dementia had a greater increase, followed by a greater decrease, in systolic BP. Both of these trends are modied by antihypertensive therapy
Stewart et al. (2009) The Honolulu-Asia Aging Study (HAAS) USA
1890 men, aged 7798 years
MMSE, Mini-Mental State Examination; VF, verbal uency; TMT-B, Trail-Making Test-B; TICS, Telephone Interview of Cognitive Status; EBMT, East Boston Memory Test; 3MS, Modied Mini-Mental State Examination; DST, digit symbol test; BSRT, Buschke Selective Reminding Test; VRT, Visual Retention Test; WAIS, Wechsler Adult Intelligence Scale; FOME, Fuld Object Memory Evaluation; APOE, apolipoprotein E; CIND, cognitive impairment no-dementia; aMCI, amnestic MCI; naMCI, non-amnestic MCI; CASI, Cognitive Abilities Screening Instrument; WMS, Wechsler Memory Scale; MAE, Multilingual Aphasia Examination; CVD, cerebrovascular disease.
405
406
Fig. 1. Overview of the principal underlying mechanisms linking the metabolic syndrome (MetS) and its components to Alzheimers disease (AD). LDL = low density lipoprotein; Hyper-TG = hypertrigliceridemia; RAAS = reninangiotensinaldosterone system; AGEs = advanced glycation endproducts; IR = insulin resistance; sAPP = soluble amyloid precursor protein ; sAPP = soluble amyloid precursor protein ; APP = amyloid precursor protein; A = -amyloid; BACE1 = -site APP-cleaving enzyme 1; AICD = APP intracellular domain; ROS = reactive oxygen species; RAGE = receptors of advanced glycation endproducts; LRP = low density lipoprotein receptor-related protein; ZO-1 = zonula occludens-1; BBB = bloodbrain barrier; IDE = insulin-degrading enzyme; PI3k = phosphoinositide kinase-3; Akt/PKB = protein kinase B; GSK-3 = glycogen synthase kinase-3 ; JNK = c-jun N-terminal kinase; ERK = extracellular signal regulated kinase; LTP = long-term potentiation.
factor (VEGF)] (Trayhurn and Wood, 2005). In addition to adipsin and leptin, the list includes a number of cytokines [interleukin (IL)-1 , IL-6, IL-10, and transforming growth factor- (TGF )], chemokines [IL-8, monocyte chemotactic protein-1 (MCP-1), and macrophage migration inhibitory factor (MIF )], acute phase proteins [PAI-1, haptoglobin and serum amyloid A (SAA)] and angiogenic factors (VEGF) (Rajala and Scherer, 2003). Adipokines linked to inammation and the inammatory response with obesity include TNF , IL-6, PAI-1-, haptoglobin and leptin and your expression, production and release is increased in adipose tissue. The major exception to this pattern is adiponectin an insulinsensitizing and anti-atherogenic fat-secreted factor, which levels decline in obesity; given the anti-inammatory action of the hormone (Ouchi et al., 2003), this exacerbates the degree to which adipose tissue is in a state of inammation in the obese (Trayhurn and Wood, 2005). Most recently, amyloid precursor protein (APP) has been introduced as a novel proinammatory adipokine which might link obesity, insulin resistance, inammation, and dementia (Lee et al., 2008). Adipose tissue processing of APP is a potential link between increased body weight and AD. Thus, APP and its fragments A 40 and A 42 are expressed in fat tissue, and overexpressed in subcutaneous abdominal adipocytes from obese patients (Lee et al., 2008). Moreover, APP synthesis was independently correlated to indices of insulin resistance in vivo and with expression of proinammatory genes including MCP-1, macrophage inammatory protein-1 , and IL-6. It is interesting to note in this context that APP cross-linking induced the release of the proinammatory cytokines IL-1b, IL-6, and IL-8 in monocytic lineage cells (Sondag and Combs, 2006). In addition, it has long been known that insulin, A 40, and A 42 directly compete for insulin-degrading enzyme (IDE) (Qiu et al., 1998) and binding to the insulin receptor (Xie et al., 2002) (Fig. 1). Another important adipokine is leptin that regulates appetite, energy balance, and neuroendocrine function. It has also been implicated in bone and brain development (Harvey, 2003). Reports of pronounced anorexia in demented patients may suggest early onset of variation and potential dysregulation in brain cen-
tres responsible for feeding behavior, bodyweight control and set-points, and energy metabolism. One hypothesis linking the establishment of bodyweight set-points and feeding behavior to bodyweight disturbances in AD is involvement of hippocampal formations e.g., CA1 (cornu ammonis) directly affected by adipose-derived hormones, such as leptin. A growing body of research suggests that leptin may play a role in learning and cognition given that leptin receptors and mRNA are widely expressed in the human brain, including the hippocampus and neocortex (Funahashi et al., 2003). In animal models, impairment of leptin receptor function in the hippocampus reduces long-term potentiation (LTP), long-term depression (LTD), and spatial memory (Li et al., 2002) (Table 2). Moreover, direct administration of leptin into the dentate gyrus enhances LTP in rats (Wayner et al., 2004), while direct leptin administration into the CA1 region of the hippocampus improves spatial memory and learning in mice (Farr et al., 2006) (Table 2). At the cellular level, leptin has been shown to enhance N-methyl-D-aspartate (NMDA) receptor function (Shanley et al., 2001), possibly through rapid trafcking of NMDA receptors to the plasma membrane (Harvey et al., 2006), in a manner analogous to insulin (Skeberdis et al., 2001). Recent work reveals that leptin may be linked to AD through modulation of A production and clearance (Fewlass et al., 2004). Leptin was found to reduce production of A , apparently through a reduction in -secretase activity, as well as to increase APOE-mediated clearance of A brils. Most interestingly, leptin administered to AD transgenic mice led to a signicant reduction in total brain A load (Fewlass et al., 2004). The potential link between leptin, nutrition and cognition was also examined in a recent study in which it was observed that leptin reverses the deleterious effects of severe diet restriction, modulating cognitive ability through 5 adenosine monophosphate-activated protein kinase (AMPK) signaling pathways (Dagon et al., 2005). Indeed, leptin has been found to act as an anti-apoptotic hormone under stress conditions in the wellcharacterized human neuroblastoma cell line SK-N-SH-SY5Y, as an in vitro model system (Russo et al., 2004). Therefore, these ndings might suggest that in vivo leptin might also be involved in
407
Table 2 Principal ndings in animal models of metabolic syndrome (MetS) and its components [abdominal obesity, impaired glucose tolerance (IGT) and/or type 1/type 2 diabetes mellitus (T1DM/T2DM), hypertension, and hyperlipidemia] and the related brain changes observed in these models. MetS or MetS components Abdominal/central obesity Li et al. (2002) Farr et al. (2006) Leptin receptor-decient rodents (Zucker rats and db/db mice) SAMP8 mice with elevated A and learning and memory impairments by 12 months of age, and normal outbred CD-1 mice T1DM (streptozotocin-injected) mouse models Both animal models showed impairments in LTP and LTD, in hippocampal CA1 neurons, as well as decits in spatial memory Leptin administration into the CA1 region of the hippocampus improved memory processing in mice performing T-maze footshock avoidance and step down passive avoidance tests Reference Animal models Principal ndings and related brain changes
IGT or T1DM/T2DM Planel et al. (2007) Insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity In both insulin-decient rats (streptozotocin-injected) and insulin-resistant mice (db/db), diabetes impaired hippocampus-dependent memory, LTP at perforant pathdentate gyruscsynapses and adult neurogenesis in the dentate gyrus, and the adrenal steroid corticosterone contributed to these adverse effects Tau phosphorylation is increased in the cortex and hippocampus of db/db mice compared with db + control mouse brain. In T1DM mouse model tau phosphorylation was also increased; however, the increase was less signicant compared with the T2DM mouse model, and more importantly, no tau cleavage was detected In these rats were found stress-compatible circulating levels of corticosterone, associated with a down-regulation of glucocorticoid receptor in the hippocampus Hypertension produced subclinical pathologic changes in the brain before the appearance of acute events such as strokes. Furthermore, in this animal model was observed white and gray matter related progressive decline in cognitive function Mice lacking Nox2 did not develop oxidative stress, cerebrovascular dysfunction, or behavioral decits. These improvements occurred without reductions in brain Ab levels or amyloid plaques., providing a link between the neurovascular dysfunction and cognitive decline associated with amyloid pathology Tau protein in the brains of these mice was hyperphosphorylated in a site-specic manner, accompanied by enhanced activity of MAPK Abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the MAPK-signaling pathway and site-specic phosphorylation of tau in vivo, leading to tauopathy in NPC Obese mice were unable to respond to peripherally administered leptin while responded to centrally administered leptin, probably for a defect in leptin transport across the BBB, suggesting that TGs could inhibit leptin transport into the brain
Stranahan et al. (2008)
T1DM (streptozotocin-injected) and T2DM (db/db) mouse models
Kim et al. (2009)
T1DM (streptozotocin-injected) and T2DM (db/db) mouse models
Beauquis et al. (2010)
T2DM GotoKakizaki rat
Hypertension Moss and Jonak (2007) Aortic coarctation model in Rhesus monkeys
Park et al. (2008)
Mice overexpressing the Swedish mutation of the APP (Tg2576) and lacking the catalytic subunit Nox2 of NADPH oxidase
Hyperlipidemia Sawamura et al. (2001) BALB/c mice carrying the genetic mutation for NPC1
Banks et al. (2004)
Mouse recombinant leptin lacking acyl coenzyme A:diacylglycerol acyltransferase 1, a critical enzyme needed to synthesize TGs
LTP: long-term potentiation; LTD: long-term depression; CA1: cornu ammonis; A : mitogen-activated protein kinase; TGs: triglycerides; BBB: bloodbrain barrier.
-amyloid; APP: amyloid precursor protein; NPC1: Niemann-Pick C1 gene; MAPK:
suppression of neuronal apoptosis and potentially participate in neurodevelopmental and neuroprotective processes. A role for leptin in neurogenesis and neurodevelopment is strengthened by the observations of Udagawa et al. (2006) that leptin stimulated the proliferation of precursor cells committed to neuronal differentiation, and promoted neuronal terminal differentiation. A recent study suggested that leptin serves a neurotrophic function in the developing and adult hippocampus by enhancing mitochondrial resistance to apoptosis and excitoxicity (Guo et al., 2007). Further supporting leptins antiapoptic function, leptin has been shown to be neuroprotective against ischemic cell injury as well as dopaminergic cell death (Weng et al., 2007; Zhang et al., 2007). Data from animal model suggest that leptin protects against delayed ischemic neuronal death in the hippocampal CA1 by following transient global cerebral ischemia in rats maintaining the pro-survival states of Akt a master protein and extracellular signal regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) signaling path-
ways (Zhang and Chen, 2008). Data from obese humans and animals indicated a chronic elevation of leptin levels associated to a leptin resistance status that involved defects both prior to leptin receptor activation as well as at the receptor and post-receptor levels (Zhang and Chen, 2008). Consequently, there are an inability of peripheral leptin to reach the hypothalamus, a decreased hypothalamic leptin receptor number and impaired leptin signal transduction (Zhang and Scarpace, 2006). In fact, genetically obese rodents with dysfunctional leptin receptors have impaired hippocampal LTP and long-term depression (LTD), and perform poorly on spatial memory tasks (Gerges et al., 2003). Therefore, chronic increase of leptin in obese status reproduces a down-regulation of this pathway, above mentionated, makes brain structures more sensible to vascular injuries. Recently, ndings from the Health ABC study conrmed the neuroprotective role of leptin levels in the elderly individuals, against cognitive decline, but also suggested that leptin resistance may play a role in the cognitive impairment (Holden et al., 2009).
408
Moreover, once established a leptin resistance status, this inuenced negatively not only cognitive performances but also the metabolic response. In fact, in vivo studies have shown that leptin improved insulin sensitivity (Ogawa et al., 1999). Additionally, leptin has been shown to have an antidiabetic function through control of intracellular fatty acid metabolism, maintenance of glucose sensitivity, and prevention of islet lipotoxicity (Shimabukuro et al., 1997). This double action of leptin on cognitive performances and metabolism suggested not only the link but also the complexity of mechanisms subtending to a MCS (Fig. 1). Abdominal obesity is a source of other hormones that play a crucial role in cognitive impairment. 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD-1) might be increased in obeses, inducing local production of cortisol, a key hormone in the differentiation of preadipocytes into adipocytes (Masuzaki et al., 2001). Glucocorticoids act via binding to glucocorticoid receptors of two subtypes, i.e., mineralocorticoid (MR, type I) and glucocorticoid (GR, type II) receptors (Elgh et al., 2006). The associations between episodic memory and glucocorticoid levels are of main interest. The hippocampal formation also forms part of the limbic HPA (LHPA) axis, a negative feedback loop where increased glucocorticoid (mainly cortisol in humans) levels are shut-off by activation of receptors at one or several levels of this axis. Activation of these receptors inuence neurochemistry, neuronal excitability, and structural plasticity (McEwen, 2000). Notably, excessive glucocorticoid exposure to hippocampal neurons impairs neuronal plasticity and may contribute to worsen neurodegeneration. This has been suggested to result in a vicious circle, where loss of neurons in the hippocampus leads to further loss of feedback inhibition leading to hypercortisolism with progressive hippocampal damage (Seckl and Olsson, 1995). Interestingly, glucocorticoid levels show an inverted Ushaped curve regarding neurophysiological function, notably LTP, and memory performance; i.e. an optimum level of glucocorticoids seems to exist for these functions. This has been suggested to be linked to activation of MR and GR receptors, whereby increased hormone levels have adverse effects through extensive activation of GR (Seckl and Olsson, 1995). Moderate increases in glucocorticoid levels may induce abnormalities in physiological functions and morphological changes such as decreased LTP, decreased neurogenesis and dendritic atrophy (McEwen et al., 1999). On a long-term basis, increased glucocorticoid exposure may accelerate neuronal damage, induced by various insults. Even moderate increases in glucocorticoid levels may induce cellular injury in targets made vulnerable by a neurodegenerative process. Recently, a cross-sectional study conducted on 16 patient with mild to moderate AD using the dexamethasone suppression tests, found a clear link between hippocampal volume notably of the CA1 region memory (episodic and visuospatial) and decreased feedback sensitivity in the LHPA axis in AD (Elgh et al., 2006), supporting a role for hypercortisolism and cognitive impairment. 2.2. Impaired glucose tolerance, type 2 diabetes mellitus, and cognitive decline 2.2.1. Insulin resistance and Alzheimers disease Impaired glucose tolerance is another component of MetS, and individuals with prediabetes are dened as those presenting impaired fasting glucose and/or impaired glucose tolerance (Yaffe et al., 2004b; Roriz-Filho et al., 2009), what increase their risk of developing frank diabetes mellitus. Those subjects already present insulin resistance as a pathophysiological mechanism that is often associated with MetS (Yaffe et al., 2004b; Roriz-Filho et al., 2009). It is of great interest that impaired fasting glucose and abnormal glucose tolerance have also been associated with impaired cognitive
performance and greater risk of developing cognitive impairment (Roriz-Filho et al., 2009). Except for the World Health Organization (WHO) criteria (Alberti and Zimmet, 1998), the European Group for study of Insulin Resistance (EGIR) criteria (Balkau and Charles, 1999), and the American Association of Clinical Endocrinologists (AACE) criteria (Einhorn et al., 2003), the denitions of MetS do not include any reference to insulin resistance or hyperinsulinemia despite clear evidence that these factors play a causal role in its occurrence in most patients (Reaven, 1988), even if the presence of insulin resistance cannot be taken for granted in patients with MetS. Insulin resistance and subsequent hyperinsulinaemia have been found to increase the risk of AD and promote decline in memory and cognitive dysfunction (Watson and Craft, 2003; Luchsinger et al., 2004). Multiple studies have shown that diabetes mellitus and prediabetes increases risk of developing cognitive decline and MCI (Vanhanen et al., 1998; Gregg et al., 2000; Yaffe et al., 2004b; Kanaya et al., 2004; Grodstein et al., 2001) (Table 1). In particular, several studies on patients with impaired glucose tolerance have shown them to have increased risk for AD (Kuusisto et al., 1997), and increased odds for VaD (Curb et al., 1999) (Table 1), as compared with control subjects. However, some studies did not show an association between insulin resistance and cognitive decline. In fact, the HonoluluAsia Aging Study (HAAS) assessed 2568 JapaneseAmerican men over an average of 5.1 years and found that dementia risk was comparably increased in those in the lowest and highest tertiles of fasting insulin (Peila et al., 2004). Furthermore, not all studies found that patients with prediabetes performed worse from a cognitive point of view than normoglycemic individuals (Fontbonne et al., 2001; Lindeman et al., 2001; Kumari and Marmot, 2005) (Table 1). Moreover, increased peripheral insulin in nondiabetics is associated with reduced AD-related brain atrophy, cognitive dysfunction, and dementia severity (Burns et al., 2007), suggesting that insulin signaling may play a role in the pathophysiology of AD. In fact, both low and high insulin levels may reect insufcient insulin signaling at the cellular level, which may result in an aberrant signaling cascade. Thus, reductions in insulin signaling, or the subsequent cascade of events associated with insulin signaling, may be the common feature that unies these apparent contradictory results (Peila et al., 2004). Insulin inuenced also A peptide metabolism by accelerating its trafcking to the plasma membrane from the trans-Golgi network, where it is generated. In addition, insulin increases extracellular levels of A by promoting its secretion and inhibiting its degradation by IDE and, nally disrupting physiological processing of A (de la Monte, 2009). These effects of insulin on A metabolism are mediated by downstream signaling through ERK MAPK (Gasparini et al., 2002). At the same time, A can adversely affect insulin signaling by competing with and inhibiting insulin binding or reducing the afnity of insulin binding to its own receptor (Xie et al., 2002). Therefore, since A competes with insulin for receptor binding, inefcient degradation of soluble A could represent an important mediator of brain insulin resistance in AD through competitive mechanism with IDE (Fig. 1). Studies in situ demonstrated increased IDE immunoreactivity surrounding SPs (Bernstein et al., 1999), and reduced IDE expression in AD hippocampi (Cook et al., 2003), while studies on transgenic mice that over-express mutant IDE demonstred a development of hyperinsulinemia, glucose intolerance, and increased levels of A in the brain. If A interferes with IDE function, the outcome should be to increase rather than decrease insulin levels and actions in the CNS. Nonetheless, in AD the opposite is true: increased levels of A are associated with reduced levels of CNS insulin and IGF-1 (Rivera et al., 2005). This suggests that is possible a dual mechanisms of cognitive impairment and neurodegeneration mediated by insulin resistance and that may be distinguished the brain insulin de-
409
ciency action from peripheral insulin resistance as into T2DM, obesity, and non-alcoholic steatohepatitis (NASH). Since there are a strongly debate about the really existence of a denition of AD as type 3 diabetes mellitus (T3DM), we propose the term MCS, not as a clinical construct but rather as a pathophysiological model on which to better understand every aspect of metabolic disorders linked to cognitive decline of vascular or degenerative origin also when not all MetS components are present. Insulin resistance also promotes lipolysis, and lipolysis generates toxic lipids, i.e. ceramides. Ceramides are lipid signaling molecules with wide-ranging modulatory effects, including cell proliferation, motility, plasticity, inammation, apoptosis, and insulin resistance; further impair mitochondrial function, and cell viability (Holland and Summers, 2008). In particular, ceramides caused insulin resistance by activating pro-inammatory cytokines and inhibiting insulin-stimulated signaling through PI3k/Akt also in the brain (de la Monte, 2009). Since ceramides, sphingosines, and other toxic lipids are lipid soluble and therefore can readily cross the BBB, some authors hypothesized that ceramides generated in neurodegeneration by precipitating a cascade leading to brain insulin resistance and increased oxidative stress, DNA damage, and lipid peroxidation (de la Monte et al., 2009). Further preliminary studies showed that intraperitoneal injection of bioactive ceramides impaired learning and caused brain insulin resistance, similar to the effects of T2DM and NASH. These observations supported the hypothesis that ceramides generated in extra-CNS tissues, particularly liver, can cause brain insulin resistance and thereby mediate neurodegeneration generating a virtual pathological axis to link abdominal organ with the brain. These suggestions were conrmed by an increase in ceramide accumulation in the vulnerable brain regions (middle frontal gyrus) but not in nonvulnerable brain regions of autopsy-conrmed AD patients compared with age-matched controls (Cutler et al., 2004). Recent literature suggested that the brain itself synthesized locally someone molecules intervening in metabolism regulation (Gerozissis, 2008), adding a new dimension in the investigation of the physiopathology of cognitive disorders. In this cascade of events, insulin has an important implication on cognitive and metabolic impairment. Data available from animal studies demonstrated an impact of enriched in fat diet on expression of mRNA encoding for insulin and modications of the intracellular insulin signaling pathways, in the hypothalamus (Gerozissis, 2008). The brain insulin impairment might be not only a consequence but also a starting point for the development of metabolic dysfunction. The mechanisms by which insulin resistance intervenes in the AD pathogenesis appeared to be different. First, insulin and IGF-1 supported cytoskeletal functions via phosphorylation (Hong and Lee, 1997), which is required for cytoskeleton assembly and stabilization of microtubulis (Mts) and several insulin kinases stimulated were responsible for physiological phosphorylation of tau protein, as ERK MAPK and cyclin dependent kinase 5. Recently, in a mice model of type 1 diabetes mellitus (T1DM) with induced insulin deciency with streptozotocin injection, Planel et al. (2007) has founded that impaired insulin signaling can result in tau hyperphosphorylation through two distinct mechanisms. One was temperature-independent, inherent to insulin depletion, and probably caused to inhibition of phosphoinositide kinase-3 (PI3k)/Akt (or protein kinase B, PKB) pathway, in particular by inhibition of phosphatase activity (PP2A) and increased activation of glycogen synthase kinase-3 (GSK-3 ) (Schubert et al., 2003) (Fig. 1). In addition, inhibition of insulin/IGF-1 signaling blocked the Wnt pathway (Doble and Woodgett, 2003), which negatively regulated GSK-3 via a PI3K/Akt-independent mechanism. In AD, both PI3k/Akt and Wnt signaling have been linked to key molecular abnormalities (De Ferrari and Inestrosa, 2000). The other mechanism was consequent to hypothermia. In fact, in the later phase of diabetes mellitus,
decits in peripheral glucose/energy metabolism lead to relative hypothermia. This leads to another direct inhibition of PP2A activity by low temperatures, resulting nally in massive hyperphosphorylation of tau (Planel et al., 2007). Hyperphosphorylated tau protein cannot be transported into axons, and instead accumulated and aggregated in neuronal perikarya and since it cannot bound to MTs, destabilized the MT network, inducing MT disruption (Feinstein and Wilson, 2005). Aberrant intra-neuronal phosphotau accumulation contributes to neurodegeneration by enhancing oxidative stress, and triggering pathophysiological cascades that lead to increased apoptosis, mitochondrial dysfunction, and necrosis (Mandelkow et al., 2003). More recently, tau phosphorylation is increased in the cortex and hippocampus of db/db mice (an animal model of T2DM) compared with db + control mouse brain. Interestingly, there is an age-dependent increase in tau cleavage that is not observed in age-matched control db + animals. Streptozotocin injection also induced tau hyperphosphorylation in T1DM mice; however, the increase was less signicant compared with the T2DM mouse model, and more importantly, no tau cleavage was detected (Kim et al., 2009). These results suggested that T1DM 1 and T2DM may contribute to AD through different mechanisms; in T2DM, hyperglycemia-mediated tau cleavage may be the key feature, whereas insulin deciency may be the major contributing factor in T1DM. An important result about a role of neuroendocrine system in diabetes-induced cognitive dysfunction was provided by Stranahan et al. (2008) which have been demonstred that, in both insulin-decient rats and insulin-resistant mice, diabetes impaired hippocampus-dependent memory, LTP at perforant pathdentate gyruscsynapses and adult neurogenesis in the dentate gyrus, and the adrenal steroid corticosterone contributed to these adverse effects. In fact, rats treated with streptozocin have reduced insulin and showed hyperglycemia, increased corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar decits were observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone and obesity. Changes in hippocampal plasticity and function in both animal models were reversed when normal physiological levels of corticosterone were maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated decits in neurogenesis and synaptic plasticity (Stranahan et al., 2008). Finally, impaired insulin signaling, increased oxidative stress by expression of pro-oxidant genes such as NOS and NOX, DNA damage with apoptosis, incorporation of 8-OHdG, which destabilizes DNA, lipid peroxidation manifested by 4-hydroxynonenal (HNE) accumulation, activation of pro-apoptosis genes, energy metabolism dysfunction by reduced expression of mitochondriaencoded genes (de la Monte and Wands, 2005). In fact, the progressive worsening of insulin/IGF resistance with stage of AD is correlated with all this cellular alterations but in different manner according to the insulin resistance disease is in or outside the CNS. Low density lipoprotein receptor-related protein (LRP)-1 is known to function as a BBB clearance (or efux) transporter for A modulated by APOE and apolipoprotein J (Zlokovic, 1996) (Fig. 1). N-terminal cleavage of LRP by -secretase releases soluble LRP (sLRP) into the plasma, where it binds to A . sLRP may be a key mediator of peripheral A clearance. Peripherally administered recombinant LRP blocked A transport across the BBB in mice and reduced brain A 40 and A 42 levels, brain vascular A levels, and amyloid burden by 90%. Patients with AD had a 30% decrease in sLRP, a 280% increase in the proportion of oxidized sLRP (which has a lower afnity for A ), and large increases in the percentage of free plasma A 40 and A 42 (Jaeger et al., 2009). Insulin modulates LRP expression and translocation to the plasma membrane, where it may more readily encounter -secretase and produce sLRP. In rats, insulin rapidly increased both hepatic expression of LRP1 in
410
the plasma membrane fraction and hepatic uptake of A 40. Insulin resistance may interfere with this translocation, reducing levels of sLRP or increasing sLRP oxidation (Craft, 2009). Thus, increased hormonal activity especially of the 11 HSD-1 resulted indeed in increased angiotensinogen (AGT) gene expression, at least in mouse adipose tissue suggesting a causal relationship between obesity and hypertension more than a simple co-occurrence into inside of MetS. Other molecular systems were involved in this link between obesity and hypertension. Obesity is characterized by hemodynamic changes for increased of plasma and stroke volumes and increased cardiac output. Two main antagonistic circulating regulatory systems, the reninangiotensinaldosterone system (RAAS) and the cardiac natriuretic peptide system (CNPS) are dysregulated in obesity explaining the high cardiac output as well as the relatively increased vascular resistances in obese hypertensive patients (Sarzani et al., 2008). Moreover, these cardiovascular regulatory systems are involved not only in the regulation of sodium retention and BP, but also in some aspects of obesity-associated metabolic derangements (Engeli and Sharma, 2001). There is also evidence that overactivation of RAAS might contribute to the pathogenesis of AD by angiotensin II (AT2) which in the brain continues conversion to angiotensin IV (Savaskan, 2005) The latter act through angiotensin receptor 4 (also known as insulin-regulated aminopeptidase, IRAP) enhanced learning and memory in animal models (Albiston et al., 2001). 2.2.2. Type 2 diabetes and cognitive decline: linking mechanism Diabetes mellitus is a systemic disease that can damage any organ in the body, and these organic lesions may lead to hypertension, renal failure, vision loss, autonomic and peripheral neuropathy, peripheral vascular disease, myocardial infarction and cerebrovascular disease (CVD), including stroke (Zhao et al., 2010). Furthermore, also the occurrence of diabetes and dementia is very high in older patients, suggesting a possible link between the two, overall because diabetic patients have a higher chance of developing dementia (Table 1). Several population-based studies examined the relation of T2DM with predementia syndromes (MCI, amnestic MCI, nonamnestic MCI, and vascular cognitive impairment nodementia) with contrasting ndings (Luchsinger et al., 2001, 2007b; MacKnight et al., 2002) (Table 1). T2DM has been also found consistently to be related to VaD but its relation to AD is less clear, although half of the studies found an increased risk in diabetic patients (Leibson et al., 1997; Ott et al., 1999; Xu et al., 2004; Luchsinger et al., 2005; Luchsinger and Gustafson, 2009) (Table 1). Moreover, both AD and T2DM shared several clinical and biochemical features, particularly important amongst these was an impaired insulin signaling, suggesting overlapping pathogenic mechanisms (Gtz et al., 2009). Additionally, both AD and T2DM are conformational diseases that are characterized by deposits of insoluble protein aggregates (Jones et al., 2009). Interestingly, disease progression in T2DM, characterized by progressive insulin resistance of target tissues leading to progressively elevated plasma glucose levels, is also accompanied by deposition of the amyloidogenic protein amylin in insulin-producing pancreatic -cells (Calcutt et al., 2009). Multiple possible mechanisms may hence underpin the association between diabetes and AD, including direct effects of hyperglycemia to the brain, neuronal insulin receptor desensitization, and insulin-induced A amyloidosis within the brain, in addition to indirect ischemic effects, such as T2DM-promoted CVD. A recent effective treatment strategy in T2DM is the use of incretinbased therapies based on the actions of the physiological peptide, glucagon-like peptide-1 (GLP-1) on its receptor (GLP-1R), utilizing the long-acting analog exendin-4 (Ex-4) (Lovshin and Drucker, 2009). GLP-1R agonists acutely act on -cells to stimulate insulin gene transcription and glucose-dependent insulin release. Chronic
actions include stimulation of -cell proliferation, induction of islet neogenesis, and inhibition of -cell apoptosis that, together, promote expansion of -cell mass and the normalization of insulin signaling (Li et al., 2010). GLP-1R is expressed widely and its activation results in multiple biological responses. GLP-1R stimulation in brain is classically allied to regulation of appetite and satiety to neurotrophic (Perry et al., 2002a) and neuroprotective actions in both cellular and in vivo models of acute and chronic neurodegenerative conditions (Perry et al., 2002b), including stroke (Li et al., 2010), AD (Perry et al., 2003), and Parkinsons disease (Li et al., 2010). GLP-1 and Ex-4 have been reported to acutely reduce brain levels of A following their intracerebroventricular administration to mice to impact memory and modulate synaptic plasticity. Each of these actions is relevant to AD and may additionally be impacted by T2DM (Li et al., 2010). The pathogenic effect of high glucose is mediated to a signicant degree via an increased production of nitrogen and reactive oxygen species (ROS) and subsequent oxidative stress (Roriz-Filho et al., 2009) (Fig. 1). Like A , this oxidative stress, can inict cellular damage and activate a number of cellular stress-sensitive pathways to induce cellular dysfunction both directly or via increased advanced glycation endproducts (AGEs), the products of nonenzymatic glycosylation and oxidation of proteins and lipids. AGEs formed primarily by the reaction of sugars with the amino groups of lysine and arginine accumulated in normal aging and in many diseases and pro-oxidant states and they interacted with their receptors (RAGE) (Yan et al., 2009). RAGE is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for A on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE was observed in regions of the brain affected by AD, and A -RAGE interaction in vitro leaded to cell stress with the generation of ROS and activation of downstream signaling mechanisms including the MAPK pathway. RAGE-mediated activation of p38 MAPK in neurons causes A -induced inhibition of LTP in slices of entorhinal cortex (Fig. 1). Increased expression of RAGE in an A -rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant APP. Interception of A interaction with RAGE, by infusion of soluble RAGE, decreases A content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of A accumulation. These data suggested that RAGE may be a therapeutic target for AD (Yan et al., 2009). A efux transport across the BBB is a critical pathway for A clearance from the brain but A transport appears to be bi-directional. A BBB efux transport is via the LRP-1 and Pglycoprotein (P-gp) whereas inux transport is by RAGE (Deane et al., 2004). RAGE expression has been shown to increase in AD (Donahue et al., 2006) and chronic inammatory diseases (e.g., diabetes mellitus, atherosclerosis, and cardiovascular disease). Upregulation of RAGE expression is mediated by several ligands including AGEs and A , and by cytokines such as IL-1 and TGF by activating nuclear factor- B (NF- B) (Silverberg et al., 2010). Expression of the capillary amyloid efux transporter LRP is decreased, whereas the expression of the amyloid inux transporter RAGE is increased (Donahue et al., 2006). Furthermore, there is a progressive increase in microvessel RAGE expression from controls through early stage AD to late stage AD (Miller et al., 2008). In diabetes, RAGE is over-expressed and binds AGEs, resulting in damage to multiple cell functions (Ramasamy et al., 2005). A also interacts with RAGE, and endothelial RAGE expression increases dramatically in AD. A triggers dysregulation of calcium homeostasis directly through the formation of pores or indirectly by modulating voltage-gated calcium channels or G-protein coupled receptors. A rise in intracellular Ca concentration activates the S100
411
proteins wich interact with glial brillary acidic protein extracellular space, forming dimers and oligomers and partecipating in inammation (Leclerc et al., 2009). Interestingly, at sites of inammation, oxidative stress enahances the formation of AGEs. In this context, A , AGEs and s100 proteins interact with RAGE and modulate MAPK pathways, such as c-jun N-terminal kinase (JNK), ERK, and p38, leading to caspase activation and neuronal apoptosis (Leclerc et al., 2009) (Fig. 1). Furthermore, RAGE-mediated JNK activation can also enhance GSK-3 activity by altering Wnt signaling pathway resulting in tau hyperphosphorylation and NFT formation (Esposito et al., 2008) (Fig. 1). Finally, transthyretin (TTR) is also present in the AD brain and is suggested to be neurotrophic. However, TTR has been shown to activate NF- B and to induce neuronal apoptosis in a RAGE-dependent manner (Leclerc et al., 2009). Further studies are necessary to determine whether these same ndings are present in aging human brains. If so, this increased age-related microvessel RAGE expression may be a signicant part of the explanation as to why aging is the most important single risk factor for the development of AD. Another mechanism to explain the relationship between diabetes or impared fasting glucose could be via activation of -site APP cleaving enzyme 1 (BACE1). A is derived from APP via cleavage by two proteases, - and -secretase. The -secretase has been identied as a novel aspartic protease named BACE1 that initiates A formation. Importantly, BACE1 appears to be dysregulated in AD. In a genetic animal model for T2DM, BACE1 activity and A generation increased in the brain (Li et al., 2007). Another study concluded that T2DM exacerbated post-stroke dementia possibly due to brain injury and synergistic generation of A via activation of BACE1 (Zhang et al., 2009). 2.3. Hypertension, elevated blood pressure, and cognitive decline Hypertension is dened as a persistent systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg (Chobanian et al., 2003). Its prevalence is estimated to be around 65% among people aged 65 years and over (Kearney et al., 2005). Hypertension is the major player for CVD and the second most important risk factor, after age, for haemorrhagic and ischemic stroke (Veglio et al., 2009). Furthermore, a series of longitudinal population-based studies suggested that an higher BP at baseline was related to higher rates of cognitive decline or MCI (Elias et al., 1993; Launer et al., 1995; Tzourio et al., 1999; DeCarli et al., 2001; Tervo et al., 2004; Reitz et al., 2007) (Table 1). Chronic hypertension has been also associated with an increased risk for both VaD and AD (Duron and Hanon, 2008). Midlife high BP is associated with further cognitive decline and dementia. Conversely, in the years preceding the onset of dementia, the BP values of dementia sufferers are found to be less than or equal to those of patients who did not develop dementia (Skoog et al., 1996; Petrovitch et al., 2000; Qiu et al., 2005). In fact, longterm population-based follow-up studies have shown that high BP especially at midlife is associated with an increased AD risk later in life (Kivipelto et al., 2002; Qiu et al., 2003; Stewart et al., 2009) (Table 1). Thus, chronic hypertension predisposes to cognitive decline and dementia but a decrease in BP can be observed at the onset of dementia and during the dementias process progression. Exposure to risk factors in midlife probably better reects the total amount of exposure throughout a lifespan than does a single measure recorded later in life (Panza et al., in press). While most previous studies assessing the risk factors for VaD focused on stroke and hypertension (Graban et al., 2009), the exact mechanism by which hypertension may cause AD has not been clearly elucidated. A possible suggestion is that hypertension leads to AD by hypertension-related pathologies, especially through vascular damage (Fig. 1). Beginning from the rst phase of an increased BP, carried out some mechanism of compensation
as the growth of smooth muscle cells in the arterial resistance vessels and enhanced media thickness. Then, from a functional point of view, in chronically hypertensive patients has been noted an impaired haemodynamic cerebrovascular reserves. Therefore, in hypertensive patients, the symptoms of cerebral hypoperfusion developed at a correspondingly higher level of mean arterial pressure than in normotensives. So, hypertension makes the brain more sensitive to ischemic injury even with normal BP values. Cerebral autoregulation response is due both myogenic and neurogenic components occurring primarily at the level of small arteries and arterioles. Myogenic autoregulation appears to be primarily responsible for cerebral autoregulation. In time, it observes of hypertensive damage are endothelias surface (above all of cerebral small arteries), and BBB. Experimental damage to the endothelium of cerebral vessels has been found to attenuate or abolish myogenic autoregulation through biochemistry system dysregulated that to enclose NO and endothelin-1. NO induces vasodilatation particularly in conditions of high intravascular ow rates that would tend to counteract the protective effects of vasoconstriction. Moreover, there is also some evidence that NO may increase the permeability of cerebral vessels via a cyclic-GMP controlled mechanism (Veglio et al., 2009). Therefore, all these processes have been linked also to insulin resistance, underlining the importance of every MetS component which interfacing one with the other as a molecular puzzle inside this physiopathological scenario. Hypertension has been positively correlated with vascular permeability accompanied with protein extravasation, a common nding in the AD brain, as well as with the number of SPs and NFTs (Milionis et al., 2008). Furthermore, reports of an interaction between age and hypertension on atrophy of the temporal and occipital regions of the brain, of high systolic BP being associated with low brain weight, and of high systolic and diastolic BP being associated with increased prevalence of the NFTs in hippocampal brain regions, are also suggestive of a role for hypertension in AD (Wang et al., 2009; Nagai et al., 2010). Hypertension-related small vessel disease includes both ischemic lesions as lacunar infarctions, leucoaraiosis, subcortical white matter lesions (WMLs) and micro-bleeds, commonly found in AD. Recently, a study conducted on Rhesus monkeys using aortic coarctation model to study the effects of hypertension on cognition in young adult primates found the occurrence of multiple microinfarcts in the brain of hypertensive monkeys and white and gray matter related progressive decline in cognitive function (Moss and Jonak, 2007) (Table 2) maybe due to reorganization of myelinated axons (Hinman et al., 2006). The authors afrmed that volumetric loss might be a consequence of damage to the BBB, because uptake of gadolinium particles into the brain, a measure of BBB integrity, was increased in middle-aged hypertensive monkeys, suggesting that the integrity of the BBB was compromised (Moss and Jonak, 2007). Another mechanism by which the hypertension could be associated to cognitive dysfunction is the involvement of large vessels. In fact, hypertension accelerates the atherosclerotic process in the large vessels with the endothelial injury and progression of atherosclerotic plaques that usually lead to stenosis and cause ischemic stroke via mechanisms thrombotic or more frequently via rupture to embolism of fragments with occlusion of distal intracranial arteries (Veglio et al., 2009). Recent reviews summarized evidence from animal models in which deposition of A is increased with hypertension and, in turn, induced vascular dysfunction that impairs functional hyperemia (Iadecola and Davisson, 2008). Interestingly, the mechanisms of A -induced cerebrovascular dysfunction are similar to those of angiotensin II and involve NADPH oxidase-derived ROS. Thus, mice lacking Nox2, one isoform the catalytic subunit of NADPH oxidase, were protected from the deleterious cerebrovascular and cognitive effects of brain A accumulation (Park et al., 2008) (Table 2).
412
2.4. Hyperlipidemia and dementia; mechanisms behind the associations Although hyperlipidemia is known to contribute to vascular disease and it may play a role in cognitive decline and dementia (Reitz et al., 2004; Panza et al., 2006), specic studies for older subjects are limited. MetS is characterized by a particular dyslipidemic panel including low HDL cholesterol and hypertrigliceridemia. In particular, most cross-sectional studies, which included subjects aged over 75 years, showed an association between increased HDL cholesterol levels and a better performance on cognitive tests (Atzmon et al., 2002; van Exel et al., 2002; Panza et al., 2006; van Vliet et al., 2009). On the contrary, one cross-sectional study and all follow-up studies, performed in larger populations, showed no association between HDL cholesterol levels and cognitive function and MCI (Yaffe et al., 2002; Henderson et al., 2003; Reitz et al., 2005, 2008). Hyperlipidemia has also been found, although not in all studies, to increase the risk of dementia. Elevated HDL cholesterol levels have been associated with a signicantly decreased risk of dementia, independent of APOE status and other potential confounding variable (Bonarek et al., 2000). On the contrary, some follow-up studies, performed in larger populations, showed no association between HDL cholesterol levels and incident dementia, AD or VaD (Tan et al., 2003; Reitz et al., 2004; Li et al., 2005). Finally, concerning hypertriglyceridemia, there is also evidence of an association between elevated triglyceride levels and cognitive functions in T2DM patients (Perlmuter et al., 1988) and in African Americans (Sims et al., 2008), but only in case-control and cross-sectional population-based studies. In the HAAS, there was also evidence of an association between triglyceride levels and an increase in the risk of dementia (Kalmijn et al., 2000). Moreover, some studies showed that the level of HDL cholesterol in the serum and in the CSF (Mulder et al., 1998) of AD patients is lower than that of controls and the decreased level is correlated with the severity of AD (Merched et al., 2000). Importantly, it should note that the CSF contains only HDL but not low density lipoprotein (LDL) or very low density lipoprotein (VLDL) (Borghini et al., 1995). A previous study demonstrated a strong correlation between CSF and serum HDL cholesterol levels, but not between CSF and serum total or LDL cholesterol levels (Fagan et al., 2000). These lines of evidence suggested that the decreased level of HDL in CNS may be associated with a risk of AD development, which was also linked to the decreased level of serum HDL cholesterol. In accordance with this notion, a recent study has shown that in the white matter of brains with AD, the A level increased whereas the cholesterol level decreases (Roher et al., 2002), suggesting the decreased level of cholesterol was associated with neurodegeneration in AD. Many groups have undertaken studies on the relationship between plasma total cholesterol (TC) levels and AD risk in humans, but without conclusive ndings (Adunsky et al., 2002; Reitz et al., 2004; Panza et al., 2006). The pathophysiological mechanisms by which dyslipidemias may increase the risk for dementia are not clear. Cholesterol is an essential component of membranes for maintaining their structure and functions. The discovery that possession of APOE allele 4 is a strong risk factor for AD leads us to focus on the role of cholesterol in the pathogenesis of AD. Cholesterol is known to interact with A in a reciprocal manner: cellular cholesterol levels modulate A generation, whereas A alters cholesterol dynamics in neurons, leading to tauopathy (Michikawa, 2003). A recent autopsy-based study revealed ndings inconsistent with the above results, i.e., it was not TC or LDL cholesterol level but low HDL cholesterol level in plasma that was associated with the increased number of SPs and NFTs (Launer et al., 2001). Hyperphosphorylation of tau is a requisite step for the formation of NFTs, one of the pathological hallmarks in the AD brain. It
is interesting to note that a perturbation of cholesterol metabolism and NFT formation coexist in brains with Niemann-Pick type C disease, a disorder of cholesterol metabolism. A model animal showed that tau in the brains of these patients was hyperphosphorylated in a site-specic manner, accompanied by enhanced activity of MAPK (Sawamura et al., 2001) (Table 2). Interestingly, a deciency in cellular cholesterol or a deciency in cholesterol supplied to neurons was shown to inhibit dendrite outgrowth and synaptogenesis, and to induce neurodegeneration as well as tauopathy (Michikawa, 2003). In addition, it was found that cholesterol deciency in lipid rafts was responsible for the induction of tau phosphorylation (Simons and Ikonen, 1997), indicating that the state of tau phosphorylation was modulated not by the total cellular cholesterol level but by that of a specic cellular compartment such as lipid rafts, leading to alteration in the intracellular signaling. Lower HDL levels are associated to altered LDL/HDL ratio which is very important to the stability of cellular membranes. In this context, it was noteworthy that oligomeric but not monomeric A affected cellular cholesterol metabolism (Michikawa et al., 2001) by generating A -lipid particles with a density identical to that of HDL, which cannot be internalized into cells (Michikawa et al., 2001). These ndings implied the central role of cholesterol in the amyloid cascade, that is, the increased level of A oligomers affects cellular cholesterol metabolism, resulting in the reduction in cholesterol levels in neurons, which in turn induces hyperphosphorylation of tau, impairment of synaptic plasticity, and nally neurodegeneration. Taken all together, it may be possible that the level of oligomeric A that can increase in an aged brain affects brain cholesterol homeostasis, which is compensated for mainly by the APOE isoform-dependent HDL cholesterol supply from astrocytes. The lower ability of APOE4 to generate HDL may result in earlier disruption in cholesterol homeostasis in neurons, leading to tauopathy. In this context, it may also be possible that the decreased HDL level in the CNS linked with a decreased level of serum HDL cholesterol is a risk factor for the development of AD (Michikawa, 2003) (Fig. 1). Plasma TG homeostasis depends on the balance between TG secretion and lipolysis, processes dysregulated in the context of MetS and that accelerate the neurodegeneration. Such changes in plasma lipids would drive the pathogenesis of AD, but, in turn, it is possible that an inherent and early feature of AD pathogenesis may include alterations in plasma lipid homeostasis that precede detectable cognitive and neuropathological changes (Burgess et al., 2006). The mechanisms by which high levels of plasma A may affect VLDL-TG secretion are not yet understood. It is possible that APOE may play a role because A binds APOE in the brain, and it has been reported to be associated with APOEcontaining lipoproteins in plasma. Importantly, APOE was required for uptake of peripherally injected A by the liver (Hone et al., 2003) and it was strongly implicated with VLDL-TG secretion in a dose-dependent manner. Other work has shown that radiolabeled exogenous A can associate with synthetic chylomicron-like lipid emulsions and is metabolized in parallel with these particles after injection into the peripheral circulation of rabbits (James et al., 2003). Furthermore, the addition of exogenous A to VLDL particles was found to alter their intracellular metabolism, such that rather than being degraded by lysosomes after endocytic uptake by the LRP in broblasts and hippocampal cells, A -VLDL particles were preferentially resecreted into culture medium (Scharnagl et al., 1999). These results suggested a model whereby hepatic uptake of A -lipoprotein complexes could result in enhanced secretion of VLDL particles, thereby elevating plasma TG levels prior to amyloid deposition (Burgess et al., 2006). Nonetheless, hypertrigliceridemia was itself a player in the pathogenesis of dementia (Zuliani et al., 2001) (Fig. 1) by other mechanisms besides a vascular damage as well as oxidative brain damage induced through lipid peroxidation.
413
Wang et al. demonstrated that TG-rich lipoprotein (TGRL) lipolysis induces ROS generation, especially superoxide anion indicating that the formation of redox signaling platforms on endothelial cell membranes may contribute to endothelial injury and that lipid raft clustering may serve as a common mechanism for transmembrane signaling. In particular, TGRL lipolysis products stimulate lipid raft clustering, which provides a platform for NADPH oxidase and increases enzyme activity and thereby stimulates the production of ROS (Wang et al., 2008). As a result, excessive ROS disrupts lipid rafts and affects raft function (e.g., eNOS), which may contribute to endothelial injury. Another possible explanation of the hypertrigliceridemia and cognitive dysfunction link come from animal studies which showed how TGs could inhibit leptin transport into the brain. Serum TGs have a rapid and immediate effect on the transport of leptin by binding leptin in the circulation or by acting directly on the leptin transporter presents on BBB. It may be that the leptin transporter possesses a regulatory site controlled by TGs. Mice lacking acyl coenzyme A:diacylglycerol acyltransferase 1, a critical enzyme needed to synthesize triglycerides, are more sensitive to infusions of leptin (Banks et al., 2004) (Table 2). Another potential pathogenic mechanism by wich hyper-TG can injure the pathogenesis of cognitive disorders is by TG lipolysis products that increased monolayer permeability striking specialized junctions between adjacent cells (Harhaj and Antonetti, 2004). In particular, zonula occludens-1 (ZO-1), a tight junction-associated protein which couples the structural and dynamic properties of the cytoskeletal network to the paracellular barrier, interacted with transcription factors and signaling molecules (Bazzoni and Dejana, 2004), activating intracellular pathways (Fig. 1). In fact, besides their key role in regulating barrier function, junctional proteins may also affect cell survival by signaling cellcell attachment. Close cell-to-cell contacts are thought to be important in anchoragedependent cells, such as endothelial cells, acting as survival signals and obviously, cleavage of this protein junctions can interrupt extracellular survival signals activating the apoptotic pathway. Interestingly, recent report indicates that TG lipolysis products can open paracellular junctions and thus may promote the accumulation of lipoproteins in the subendothelial. altering monolayer permeability concurrently with a rearrangement of the tight junction proteins ZO-1 and occludin, adherens junctional VE-cadherin, and cytoskeletal F-actin. Furthermore, this disturbance of the tight and adherens junctions precedes the activation of the apoptotic cascade and ZO-1 proteolysis (Eiselein et al., 2007).
etiologies among metabolic disorders (Craft, 2009). For example, weight loss through lifestyle interventions or medications may alter adipokine activity, improve hyperinsulinemia, inammation, glucose tolerance, BP, lipids, and the risk of CVD. Considerable interest has also arisen regarding the effects of lifestyle interventions such as exercise and dietary/nutriceutical manipulations. Pharmacological interventions currently under study include statins, antihypertensive therapies, and insulin-sensitizing drugs. If MetS and its components are associated with increased risk of developing cognitive impairment, then early identication and treatment of these individuals might offer avenues for disease course modication. Obviously, even rigid attention to these risk factors and MetS will not be able to prevent dementia altogether. Future research aimed at identifying mechanisms that underlie comorbid associations of MetS components will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing these cognitive disorders.
References
Adunsky, A., Chesnin, V., Davidson, M., Gerber, Y., Alexander, K., Haratz, D., 2002. A cross-sectional study of lipids and apoC levels in Alzheimers patients with and without cardiovascular disease. J. Gerontol. A Biol. Sci. Med. Sci. 57, M757M761. Alberti, K.G., Zimmet, P.Z., 1998. Denition, diagnosis and classication of diabetes mellitus and its complications. Part 1: diagnosis and classication of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539553. Alberti, K.G., Zimmet, P., Shaw, J., IDF Epidemiology Task Force Consensus Group, 2005. The metabolic syndrome a new worldwide denition. Lancet 366, 10591062. Albiston, A.L., McDowall, S.G., Matsacos, D., Sim, P., Clune, E., Mustafa, T., Lee, J., Mendelsohn, F.A., Simpson, R.J., Connolly, L.M., Chai, S.Y., 2001. Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase. J. Biol. Chem. 276, 4862348626. Anstey, K., Sanden, C., Salim, A., OKearney, R., 2007. Smoking as a risk factor for dementia and cognitive decline. a meta-analysis of prospective studies. Am. J. Epidemiol. 166, 367378. Atzmon, G., Gabriely, I., Greiner, W., Davidson, D., Schechter, C., Barzilai, N., 2002. Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J. Gerontol. A Biol. Sci. Med. Sci. 57, M712M715. Baccari, B.C., 2010. Orexins and gastrointestinal functions. Curr. Protein Pept. Sci. 11, 148155. Balkau, B., Charles, M.A., 1999. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet. Med. 16, 442443. Barrett-Connor, E., Edelstein, S., Corey-Bloom, J., Wiederholt, W., 1998. Weight loss precedes dementia in community-dwelling older adults. J. Nutr. Health Aging 2, 113114. Banks, W.A., Coon, A.B., Robinson, S.M., Moinuddin, A., Shultz, J.M., Nakaoke, R., Morley, J.E., 2004. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53, 12531260. Baumgartner, R.N., Heymseld, S.B., Roche, A.F., 1995. Human body composition and the epidemiology of chronic disease. Obes. Res. 3, 7395. Bazzoni, G., Dejana, E., 2004. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev. 84, 869890. Beauquis, J., Homo-Delarche, F., Giroix, M.H., Ehses, J., Coulaud, J., Roig, P., Portha, B., De Nicola, A.F., Saravia, F., 2010. Hippocampal neurovascular and hypothalamicpituitary-adrenal axis alterations in spontaneously type 2 diabetic GK rats. Exp. Neurol. 222, 125134. Bernstein, H.G., Ansorge, S., Riederer, P., Reiser, M., Frolich, L., Bogerts, B., 1999. Insulin-degrading enzyme in the Alzheimers disease brain: prominent localization in neurons and senile plaques. Neurosci. Lett. 263, 161164. Bonarek, M., Barberger-Gateau, P., Letenneur, L., Deschamps, V., Iron, A., Dubroca, B., Dartigues, J.F., 2000. Relationships between cholesterol, apolipoprotein E polymorphism and dementia: a cross-sectional analysis from the PAQUID study. Neuroepidemiology 19, 141148. Borghini, I., Barja, F., Pometta, D., James, R.W., 1995. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal uid. Biochim. Biophys. Acta 1255, 192200. Burgess, B.L., McIsaac, S.A., Naus, K.E., Chan, J.Y., Tansley, G.H., Yang, J., Miao, F., Ross, C.J., van Eck, M., Hayden, M.R., van Nostrand, W., St George-Hyslop, P., Westaway, D., Wellington, C.L., 2006. Elevated plasma triglyceride levels precede amyloid deposition in Alzheimers disease mouse models with abundant A beta in plasma. Neurobiol. Dis. 24, 114127. Burns, J.M., Donnelly, J.E., Anderson, H.S., Mayo, M.S., Spencer-Gardner, L., Thomas, G., Cronk, B.B., Haddad, Z., Klima, D., Hansen, D., Brooks, W.M., 2007. Peripheral insulin and brain structure in early Alzheimer disease. Neurology 69, 1094 1104.
3. Conclusions At present, cumulative evidence suggested that MetS appeared to increase the risk for ARCD, while for MCI and its progression to dementia the ndings were too limited to draw any conclusion. Furthermore, several studies suggested that MetS may be linked to the risk of developing dementia and VaD, while contrasting ndings existed of the possible role of MetS in developing AD. Several individual components of MetS have been linked to risk of developing dementia and cognitive impairment. In conclusion, a growing body of evidence from epidemiological and basic research has proposed a model of cognitive impairment of vascular or degenerative origin linked to MetS and metabolic disorders, and we proposed for research purpose the MCS. Elucidation of the interactions among various metabolic disorders and identication of convergent pathophysiology underlying comorbidities will likely provide important clues to dementiarelated mechanisms (Craft, 2009). The potential mechanisms linking the continuum of obesity, hyperinsulinemia, hypertension, hyperlipidemia, and T2DM are multiple, overlapping, and highly correlated. These interactive effects may provide clues to shared
414
V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417 Farr, S.A., Banks, W.A., Morley, J.E., 2006. Effects of leptin on memory processing. Peptides 27, 14201425. Ferri, C.P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang, Y., Jorm, A., Mathers, C., Menezes, P.R., Rimmer, E., Scazufca, M., 2005. Alzheimers disease international. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 21122117. Feinstein, S.C., Wilson, L., 2005. Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochim. Biophys. Acta 1739, 268279. Fewlass, D.C., Noboa, K., Pi-Sunyer, F.X., Johnston, J.M., Yan, S.D., Tezapsidis, N., 2004. Obesity-related leptin regulates Alzeimers Abeta. FASEB J. 18, 18701878. Fitzpatrick, A.L., Kuller, L.H., Lopez, O.L., Diehr, P., OMeara, E.S., Longstreth Jr., W.T., Luchsinger, J.A., 2009. Obesity: risk of dementia in the cardiovascular health cognition study. Arch. Neurol. 66, 336342. Fontbonne, A., Berr, C., Ducimetiere, P., Alperovitch, A., 2001. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the epidemiology of vascular aging study. Diabetes Care 24, 366370. Frisardi, V., Solfrizzi, V., Imbimbo, B.P., Capurso, C., DIntrono, A., Colacicco, A.M., Vendemiale, G., Seripa, D., Pilotto, A., Capurso, A., Panza, F., 2010a. Towards disease-modifying treatment of Alzheimers disease: drugs targeting -amyloid. Curr. Alzheimer Res. 7, 4055. Frisardi, V., Solfrizzi, V., Capurso, C., Kehoe, P.G., Imbimbo, B.P., Santamato, A., Dellegrazie, F., Seripa, D., Pilotto, A., Capurso, A., Panza, F., 2010b. Aluminum in the diet and Alzheimers disease: from current epidemiology to possible diseasemodifying treatment. J. Alzheimers Dis. 20, 1730. Frisardi, V., Solfrizzi, V., Capurso, C., Imbimbo, B.P., Vendemiale, G., Seripa, D., Pilotto, A., Panza, F., 2010c. Is insulin resistant brain state a central feature of the metabolic-cognitive syndrome? J. Alzheimers Dis. [Epub ahead of print]; doi:10.3233/JAD-2010-100015. Funahashi, H., Yada, T., Suzuki, R., Shioda, S., 2003. Distribution, function, and properties of leptin receptors in the brain. Int. Rev. Cytol. 224, 127. Gasparini, L., Netzer, W.J., Greengard, P., Xu, H., 2002. Does insulin dysfunction play a role in Alzheimers disease? Trends Pharmacol. Sci. 23, 288293. Gerges, N.Z., Aleisa, A.M., Alkadhi, K.A., 2003. Impaired long-term potentiation in obese zucker rats: possible involvement of presynaptic mechanism. Neuroscience 120, 535539. Gerozissis, K., 2008. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur. J. Pharmacol. 585, 3849. Gorospe, E.C., Dave, J.K., 2007. The risk of dementia with increased body mass index. Age Ageing 36, 2329. Gtz, J., Ittner, L.M., Lim, Y.A., 2009. Common features between diabetes mellitus and Alzheimers disease. Cell. Mol. Life Sci. 66, 13211325. Graban, A., Bednarska-Makaruk, M., Bochynska, A., Lipczynska-ojkowska, W., Ryglewicz, D., Wehr, H., 2009. Vascular and biochemical risk factors of vascular dementia after lacunar strokes (S-VaD) and after multiinfarcts in strategic areas (M-VaD). J. Neurol. Sci. 283, 116118. Gregg, E.W., Yaffe, K., Cauley, J.A., Rolka, D.B., Blackwell, T.L., Narayan, K.M., Cummings, S.R., 2000. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch. Intern. Med. 160, 174180. Grodstein, F., Chen, J., Wilson, R.S., Manson, J.E., Nurses Health Study, 2001. Type 2 diabetes and cognitive function in community-dwelling elderly women. Diabetes Care 24, 10601065. Grundy, S.M., Cleeman, J.I., Daniels, S.R., Donato, K.A., Eckel, R.H., Franklin, B.A., Gordon, D.J., Krauss, R.M., Savage, P.J., Smith Jr., S.C., Spertus, J.A., Costa, F., American Heart Association; National Heart, Lung, and Blood Institute, 2005. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientic statement. Circulation 112, 27352752. Guo, Z., Jiang, H., Xu, X., Duan, W., Matson, M., 2007. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J. Biol. Chem. 283, 17541763. Gustafson, D., 2006. Adiposity indices and dementia. Lancet Neurol. 5, 713720. Gustafson, D., Rothenberg, E., Blennow, K., Steen, B., Skoog, I., 2003. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch. Intern. Med. 163, 15241528. Haffner, S.M., 2006. The metabolic syndrome: inammation, diabetes mellitus, and cardiovascular disease. Am. J. Cardiol. 97, 3A11A. Harhaj, N.S., Antonetti, D.A., 2004. Regulation of tight junctions and loss of barrier function in pathophysiology. Int. J. Biochem. Cell. Biol. 36, 12061237. Harvey, J., 2003. Leptin: a multifaceted hormone in the central nervous system. Mol. Neurobiol. 28, 245258. Harvey, J., Solovyova, N., Irving, A., 2006. Leptin and its role in hippocampal synaptic plasticity. Prog. Lipid Res. 45, 369378. Henderson, V.W., Guthrie, J.R., Dennerstein, L., 2003. Serum lipids and memory in a population based cohort of middle age women. J. Neurol. Neurosurg. Psychiatry 74, 15301535. Hinman, J.D., Peters, A., Cabral, H., Rosene, D.L., Hollander, W., Rasband, M.N., Abraham, C.R., 2006. Age-related molecular reorganization at the node of Ranvier. J. Comp. Neurol. 95, 351362. Ho, R.C., Niti, M., Yap, K.B., Kua, E.H., Ng, T.P., 2008. Metabolic syndrome and cognitive decline in chinese older adults: results from the singapore longitudinal ageing studies. Am. J. Geriatr. Psychiatry 16, 519522.
Calcutt, N.A., Cooper, M.E., Kern, T.S., Schmidt, A.M., 2009. Therapies for hyperglycaemia induced diabetic complications: from animal models to clinical trials. Nat. Rev. Drug Discov. 8, 417429. Chobanian, A.V., Bakris, G.L., Black, H.R., Cushman, W.C., Green, L.A., Izzo Jr., J.L., Jones, D.W., Materson, B.J., Oparil, S., Wright Jr., J.T., Roccella, E.J., 2003. Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 42, 12061252. Colcombe, S., Erickson, K., Raz, N., Webb, A.G., Cohen, N.J., McAuley, E., Kramer, A.F., 2003. Aerobic tness reduces brain tissue loss n ageing humans. J. Gerontol. 58, 176180. Craft, S., 2009. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch. Neurol. 66, 300305. Cook, D.G., Leverenz, J.B., McMillan, P.J., Kulstad, J.J., Ericksen, S., Roth, R.A., Schellenberg, G.D., Jin, L.W., Kovacina, K.S., Craft, S., 2003. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimers disease is associated with the apolipoprotein E epsilon4 allele. Am. J. Pathol. 162, 313319. Cornier, M.A., Dabelea, D., Hernandez, T.L., Lindstrom, R.C., Steig, A.J., Stob, N.R., Van Pelt, R.E., Wang, H., Eckel, R.H., 2008. The metabolic syndrome. Endocr. Rev. 29, 777822. Curb, J.D., Rodriguez, B.L., Abbott, R.D., Petrovitch, H., Ross, G.W., Masaki, K.H., Foley, D., Blanchette, P.L., Harris, T., Chen, R., White, L.R., 1999. Longitudinal association of vascular and Alzheimers dementias, diabetes, and glucose tolerance. Neurology 52, 971975. Cutler, R.G., Kelly, J., Storie, K., Pedersen, W.A., Tammara, A., Hatanpaa, K., Troncoso, J.C., Mattson, M.P., 2004. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimers disease. Proc. Natl. Acad. Sci. USA 101, 20702075. Dagon, Y., Avraham, Y., Magen, I., Gertler, A., Ben-Hur, T., Berry, E.M., 2005. Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J. Biol. Chem. 280, 4214242148. Deane, R., Wu, Z., Zlokovic, B.V., 2004. RAGE (yin) versus LRP (yang) balance regulates Alzheimer amyloid -peptide clearance through transport across the blood-brain barrier. Stroke 35 (Suppl. 1), 26282631. DeCarli, C., Miller, B.L., Swan, G.E., Reed, T., Wolf, P.A., Carmelli, D., 2001. Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch. Neurol. 58, 643647. De Ferrari, G.V., Inestrosa, N.C., 2000. Wnt signaling function in Alzheimers disease. Brain Res. Rev. 33, 112. de la Monte, S.M., Wands, J.R., 2005. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimers disease. J. Alzheimers Dis. 7, 4546. de la Monte, S.M., 2009. Insulin resistance and Alzheimers disease. B.M.B. Rep. 42, 475481. Dik, M.G., Jonker, C., Comijs, H.C., Deeg, D.J., Kok, A., Yaffe, K., Penninx, B.W., 2007. Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care 30, 26552660. Doble, B.W., Woodgett, J.R., 2003. GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell. Sci. 116, 11751186. Donahue, J.E., Flaherty, S.L., Johanson, C.E., Duncan 3rd, J.A., Silverberg, G.D., Miller, M.C., Tavares, R., Yang, W., Wu, Q., Sabo, E., Hovanesian, V., Stopa, E.G., 2006. RAGE, LRP-1, and amyloid-beta protein in Alzheimers disease. Acta Neuropathol. 112, 405415. Duron, E., Hanon, O., 2008. Hypertension, cognitive decline and dementia. Arch. Cardiovasc. Dis. 101, 181189. Einhorn, D., Reaven, G.M., Cobin, R.H., Ford, E., Ganda, O.P., Handelsman, Y., Hellman, R., Jellinger, P.S., Kendall, D., Krauss, R.M., Neufeld, N.D., Petak, S.M., Rodbard, H.W., Seibel, J.A., Smith, D.A., Wilson, P.W., 2003. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr. Pract. 9, 237252. Eiselein, L., Wilson, D.W., Lam, M.W., Rutledge, J.C., 2007. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. Am. J. Physiol. Heart Circ. Physiol. 292, H2745H2753. Elgh, E., Lindqvist Astot, A., Fagerlund, M., Eriksson, S., Olsson, T., Nsman, B., 2006. Cognitive dysfunction, hippocampal atrophy and glucocorticoid feedback in Alzheimers disease. Biol. Psychiatry 59, 155161. Elias, M.F., Wolf, P.A., DAgostino, R.B., Cobb, J., White, L.R., 1993. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham study. Am. J. Epidemiol. 138, 353364. Engeli, S., Sharma, A.M., 2001. The reninangiotensin system and natriuretic peptides in obesity-associated hypertension. J. Mol. Med. 79, 2129. Esposito, G., Scuderi, C., Lu, J., Savani, C., De Filippis, D., Iuvone, T., Steardo Jr., L., Sheen, V., Steardo, L., 2008. S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells. J. Cell. Mol. Med. 12, 914927. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), 2001. Executive summary of the third report of the National Cholesterol Education Program (NCEP). JAMA 285, 2486 2497. Fagan, A.M., Younkin, L.H., Morris, J.C., Fryer, J.D., Cole, T.G., Younkin, S.G., Holtzman, D.M., 2000. Differences in the Ab40/Ab42 ratio associatedwith cerebrospinal uid lipoproteins as a function of apolipoprotein E genotype. Ann. Neurol. 48, 201210.
V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417 Holland, W.L., Summers, S.A., 2008. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev. 29, 381402. Holden, K.F., Lindquist, K., Tylavsky, F.A., Rosano, C., Harris, T.B., Yaffe, K., Health ABC study, 2009. Serum leptin level and cognition in the elderly: ndings from the Health ABC study. Neurobiol. Aging 30, 14831489. Hone, E., Martins, I.J., Fonte, J., Martins, R.N., 2003. Apolipoprotein E inuences amyloid-beta clearance from the murine periphery. J. Alzheimers Dis. 5, 18. Hong, M., Lee, V.M., 1997. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J. Biol. Chem. 272, 1954719553. Iadecola, C., Davisson, R.L., 2008. Hypertension and cerebrovascular dysfunction. Cell Metab. 7, 476484. Isales, C.M., Zaidi, M., Blair, H.C., 2010. ACTH is a novel regulator of bone mass. Ann. N. Y. Acad. Sci. 1192, 110116. Jaeger, L.B., Dohgu, S., Hwang, M.C., Farr, S.A., Murphy, M.P., Fleegal-DeMotta, M.A., Lynch, J.L., Robinson, S.M., Niehoff, M.L., Johnson, S.N., Kumar, V.B., Banks, W.A., 2009. Testing the neurovascular hypothesis of Alzheimers disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition. J. Alzheimers Dis. 17, 553570. James, A.P., Pal, S., Gennat, H.C., Vine, D.F., Mamo, J.C.L., 2003. The incorporation and metabolism of amyloid- into chylomicron-like lipid emulsions. J. Alzheimers Dis. 5, 179188. Janssen, I., Katzmarzyk, P.T., Ross, R., 2004. Waist circumference and not body mass index explains obesity-related health risk. Am. J. Clin. Nutr. 79, 379384. Jones, A., Kulozik, P., Ostertag, A., Herzig, S., 2009. Common pathological processes and transcriptional pathways in Alzheimers disease and type 2 diabetes. J. Alzheimers Dis. 16, 787808. Kalmijn, S., Foley, D., White, L., Burchel, C.M., Curb, J.D., Petrovitch, H., Ross, G.W., Havlik, R.J., Launer, L.J., 2000. Metabolic cardiovascular syndrome and risk of dementia in JapaneseAmerican elderly men. The Honolulu-Asia aging study. Arterioscler. Thromb. Vasc. Biol. 20, 22552260. Kanaya, A.M., Barrett-Connor, E., Gildengorin, G., Yaffe, K., 2004. Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo study cohort. Arch. Intern. Med. 164, 13271333. Kearney, P.M., Whelton, M., Reynolds, K., Muntner, P., Whelton, P.K., He, J., 2005. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217223. Kendall, T.J., Hennedige, S., Aucott, R.L., Hartland, S.N., Vernon, M.A., Benyon, R.C., Iredale, J.P., 2009. p75 Neurotrophin receptor signaling regulates hepatic myobroblast proliferation and apoptosis in recovery from rodent liver brosis. Hepatology 49 (3), 901910. Kim, B., Backus, C., Oh, S., Hayes, J.M., Feldman, E.L., 2009. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150, 52945301. Kivipelto, M., Helkala, E.L., Laakso, M.P., Hnninen, T., Hallikainen, M., Alhainen, K., Iivonen, S., Mannermaa, A., Tuomilehto, J., Nissinen, A., Soininen, H., 2002. Apolipoprotein E 4 allele, elevated midlife total cholesterol level and high midlife systolic blood pressure are independent risk factors for late-life Alzheimers disease. Ann. Intern. Med. 137, 149155. Kivipelto, M., Ngandu, T., Fratiglioni, L., Viitanen, M., Kareholt, I., Winblad, B., Helkala, E.L., Tuomilehto, J., Soininen, H., Nissinen, A., 2005. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol. 62, 15561560. Korte, S.M., Koolhaas, J.M., Wingeld, J.C., McEwen, B.S., 2005. The Darwinian concept of stress: benets of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci. Biobehav. Rev. 29, 338. Kumari, M., Marmot, M., 2005. Diabetes and cognitive function in a middle-aged cohort: ndings from the Whitehall II study. Neurology 65, 15971603. Kuusisto, J., Koivisto, K., Mykkanen, L., Helkala, E.L., Vanhanen, M., Hanninen, T., Kervinen, K., Kesaniemi, Y.A., Riekkinen, P.J., Laakso, M., 1997. Association between features of the insulin resistance syndrome and Alzheimers disease independently of apolipoprotein E4 phenotype: cross-sectional population based study. BMJ 315, 10451049. Launer, L.J., Masaki, K., Petrovitch, H., Foley, D., Havlik, R.J., 1995. The association between midlife blood pressure levels and late-life cognitive function. JAMA 274, 18461851. Launer, L.J., White, L.R., Petrovitch, H., Ross, G.W., Curb, J.D., 2001. Cholesterol and neuropathologic markers of AD: a population-based autopsy study. Neurology 57, 14471452. Leclerc, E., Sturchler, E., Vetter, S.W., Heizmann, C.W., 2009. Crosstalk between calcium, amyloid beta and the receptor for advanced glycation endproducts in Alzheimers disease. Rev. Neurosci. 20, 95110. Lee, Y.H., Tharp, W.G., Maple, R.L., Nair, S., Permana, P.A., Pratley, R.E., 2008. Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring) 16, 14931500. Leibson, C.L., Rocca, W.A., Hanson, V.A., Cha, R., Kokmen, E., OBrien, P.C., Palumbo, P.J., 1997. Risk of dementia among persons with diabetes mellitus: a populationbased cohort study. Am. J. Epidemiol. 145, 301308. Li, X.L., Aou, S., Oomura, Y., Hori, N., Fukunaga, K., Hori, T., 2002. Impairment of long-term potentiation and spatial memory in leptin receptor-decient rodents. Neuroscience 113, 607615. Li, G., Shofer, J.B., Kukull, W.A., Peskind, E.R., Tsuang, D.W., Breitner, J.C., McCormick, W., Bowen, J.D., Teri, L., Schellenberg, G.D., Larson, E.B., 2005. Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology 65, 10451050.
415
Li, Z.G., Zhang, W., Sima, A.A., 2007. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 56, 18171824. Li, Y., Duffy, K.B., Ottinger, M.A., Ray, B., Bailey, J.A., Holloway, H.W., Tweedie, D., Perry, T., Mattson, M.P., Kapogiannis, D., Sambamurti, K., Lahiri, D.K., Greig, N.H., 2010. GLP-1 receptor stimulation reduces amyloid- peptide accumulation and cytotoxicity in cellular and animal models of Alzheimers disease. J. Alzheimers Dis. 19, 12051219. Lindeman, R.D., Romero, L.J., LaRue, A., Yau, C.L., Schade, D.S., Koehler, K.M., Baumgartner, R.N., Garry, P.J., 2001. A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico Elder Health Survey. Diabetes Care 24, 15671572. Lovshin, J.A., Drucker, D.J., 2009. Incretin-based therapies for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 5, 262269. Luchsinger, J.A., Tang, M.X., Stern, Y., Shea, S., Mayeux, R., 2001. Diabetes mellitus and risk of Alzheimers disease and dementia with stroke in a multiethnic cohort. Am. J. Epidemiol. 154, 635641. Luchsinger, J.A., Tang, M.X., Shea, S., Mayeux, R., 2004. Hyperinsulinemia and risk of Alzheimer disease. Neurology 63, 11871192. Luchsinger, J.A., Reitz, C., Honig, L.S., Tang, M.X., Shea, S., Mayeux, R., 2005. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65, 545551. Luchsinger, J.A., Patel, B., Tang, M.X., Schupf, N., Mayeux, R., 2007a. Measures of adiposity and dementia risk in elderly persons. Arch. Neurol. 64, 392398. Luchsinger, J.A., Reitz, C., Patel, B., Tang, M.X., Manly, J.J., Mayeux, R., 2007b. Relation of diabetes to mild cognitive impairment. Arch. Neurol. 64, 570575. Luchsinger, J.A., Gustafson, D.R., 2009. Adiposity, type 2 diabetes, and Alzheimers disease. J. Alzheimers Dis. 16, 693704. Komulainen, P., Lakka, T.A., Kivipelto, M., Hassinen, M., Helkala, E.L., Haapala, I., Nissinen, A., Rauramaa, R., 2007. Metabolic syndrome and cognitive function: a population-based follow-up study in elderly women. Dement. Geriatr. Cogn. Disord. 23, 2934. MacKnight, C., Rockwood, K., Awalt, E., McDowell, I., 2002. Diabetes mellitus and the risk of dementia, Alzheimers disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement. Geriatr. Cogn. Disord. 14, 7783. Mandelkow, E.M., Stamer, K., Vogel, R., Thies, E., Mandelkow, E., 2003. Clogging of axons by tau, inhibition of axonal trafc and starvation of synapses. Neurobiol. Aging 24, 10791085. Masuzaki, H., Paterson, J., Shinyama, H., Morton, N.M., Mullins, J.J., Seckl, J.R., Flier, J.S., 2001. A transgenic model of visceral obesity and the metabolic syndrome. Science 294, 21662170. McEwen, B.S., de Leon, M.J., Lupien, S.J., Meaney, M.J., 1999. Corticosteroids, the aging brain and cognition. Trends Endocrinol. Metab. 10, 9296. McEwen, B.S., 2000. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 886, 172189. Meloni, M., Caporali, A., Graiani, G., Lagrasta, C., Katare, R., Van Linthout, S., Spillmann, F., Campesi, I., Madeddu, P., Quaini, F., Emanueli, C., 2010. Nerve growth factor promotes cardiac repair following myocardial infarction. Circ. Res. 106, 12751284. Merched, A., Xia, Y., Visvikis, S., Serot, J.M., Siest, G., 2000. Decreased high density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimers disease. Neurobiol. Aging 21, 2730. Michikawa, M., Gong, J.S., Fan, Q.W., Sawamura, N., Yanagisawa, K., 2001. A novel action of Alzheimers amyloid b-protein (Ab): oligomeric Ab promotes lipid release. J. Neurosci. 21, 72267235. Michikawa, M., 2003. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimers disease? J. Neurosci. Res. 72, 141146. Milionis, H.J., Florentin, M., Giannopoulos, S., 2008. Metabolic syndrome and Alzheimers disease: a link to a vascular hypothesis? CNS Spectr. 13, 606613. Miller, M.C., Tavares, R., Johanson, C.E., Hovanesian, V., Donahue, J.E., Gonzalez, L., Silverberg, G.D., Stopa, E.G., 2008. Hippocampal RAGE immunoreactivity in early and advanced Alzheimers disease. Brain Res. 1230, 273280. Moss, M.B., Jonak, E., 2007. Cerebrovascular disease and dementia: a primate model of hypertension and cognition. Alzheimers Dement. 3 (Suppl. 2), S6S15. Mueller, W.H., Wear, M.L., Hanis, C.L., Emerson, J.B., Barton, S.A., Hewett-Emmett, D., Schull, W.J., 1991. Which measure of body fat distribution is best for epidemiologic research? Am. J. Epidemiol. 133, 858869. Mulder, M., Ravid, R., Swaab, D.F., de Kloet, E.R., Haasdijk, E.D., Julk, J., van der Boom, J.J., Havekes, L.M., 1998. Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal uid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis. Assoc. Disord. 12, 198203. Muller, M., Tang, M.X., Schupf, N., Manly, J.J., Mayeux, R., Luchsinger, J.A., 2007. Metabolic syndrome and dementia risk in a multiethnic elderly cohort. Dement. Geriatr. Cogn. Disord. 24, 185192. Nagai, M., Hoshide, S., Kario, K., 2010. Hypertension and dementia. Am. J. Hypertens. 23, 116124. Ngandu, T., von Strauss, E., Helkala, E.L., Winblad, B., Nissinen, A., Tuomilehto, J., Soininen, H., Kivipelto, M., 2007. Education and dementia what lies beneath the association? Neurology 69, 14421450. Nourhashmi, F., Deschamps, V., Larrieu, S., Letenneur, L., Dartigues, J.F., BarbergerGateau, P., PAQUID study. Personnes Ages Quid, 2003. Body mass index and incidence of dementia: the PAQUID study. Neurology 60, 117119. Ogawa, Y., Masuzaki, H., Hosoda, K., Aizawa-Abe, M., Suga, J., Suda, M., Ebihara, K., Iwai, H., Matsuoka, N., Satoh, N., Odaka, H., Kasuga, H., Fujisawa, Y., Inoue, G., Nishimura, H., Yoshimasa, Y., Nakao, K., 1999. Increased glucose metabolism and
416
V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417 Reitz, C., Tang, M.X., Luchsinger, J., Mayeux, R., 2004. Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch. Neurol. 61, 705714. Reitz, C., Luchsinger, J., Tang, M.X., Manly, J., Mayeux, R., 2005. Impact of plasma lipids and time on memory performance in healthy elderly without dementia. Neurology 64, 13781383. Reitz, C., Tang, M.X., Manly, J., Mayeux, R., Luchsinger, J.A., 2007. Hypertension and the risk of mild cognitive impairment. Arch. Neurol. 64, 17341740. Reitz, C., Tang, M.X., Manly, J., Schupf, N., Mayeux, R., Luchsinger, J.A., 2008. Plasma lipid levels in the elderly are not associated with the risk of mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 25, 232237. Rivera, E.J., Goldin, A., Fulmer, N., Tavares, R., Wands, J.R., de la Monte, S.M., 2005. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimers disease: link to brain reductions in acetylcholine. J. Alzheimers Dis. 8, 247268. Roberts, R.O., Geda, Y.E., Knopman, D.S., Cha, R.H., Boeve, B.F., Ivnik, R.J., Pankratz, V.S., Tangalos, E.G., Petersen, R.C., 2010. Metabolic syndrome, inammation, and nonamnestic mild cognitive impairment in older persons: a population-based study. Alzheimer Dis. Assoc. Disord. 24, 1118. Roher, A.E., Weiss, N., Kokjohn, T.A., Kuo, Y.M., Kalback, W., Anthony, J., Watson, D., Luehrs, D.C., Sue, L., Walker, D., Emmerling, M., Goux, W., Beach, T., 2002. Increased Ab peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimers disease. Biochemistry 41, 1108011090. Roriz-Cruz, M., Rosset, I., Wada, T., Sakagami, T., Ishine, M., De S Roriz-Filho, J., Cruz, T.R., Hosseinkhani, M., Rodrigues, R.P., Sudoh, S., Arai, H., Wakatsuki, Y., Souza, A.C., Nakagawa, M., Kita, T., Matsubayashi, K., 2007. Cognitive impairment and frontal-subcortical geriatric syndrome are associated with metabolic syndrome in a stroke-free population. Neurobiol. Aging 28 (11), 17231736. Roriz-Filho, J.S., S-Roriz, T.M., Rosset, I., Camozzato, A.L., Santos, A.C., Chaves, M.L., Moriguti, J.C., Roriz-Cruz, M., 2009. (Pre)diabetes, brain aging, and cognition. Biochim. Biophys. Acta 1792, 432443. Russo, V.C., Metaxas, S., Kobayashi, K., Harris, M., Werther, G.A., 2004. Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology 145, 41034112. Sarzani, R., Salvi, F., Dess-Fulgheri, P., Rappelli, A., 2008. Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans. J. Hypertens. 26, 831843. Savaskan, E., 2005. The role of the brain renin-angiotensin system in neurodegenerative disorders. Curr. Alzheimer Res. 2, 2935. Sawamura, N., Gong, J.S., Garver, W.S., Heidenreich, R.A., Ninomiya, H., Ohno, K., Yanagisawa, K., Michikawa, M., 2001. Site-specic phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice. J. Biol. Chem. 276, 1031410319. Scharnagl, H., Tisljar, U., Winkler, K., Huttinger, M., Nauck, M.A., Gross, W., Wieland, H., Ohm, T.G., Marz, W., 1999. The beta A4 amyloid peptide complexes to and enhances the uptake of beta-very low density lipoproteins by the low density lipoprotein receptor-related protein and heparan sulfate proteoglycans pathway. Lab. Invest. 79, 12711286. Schubert, M., Brazil, D.P., Burks, D.J., Kushner, J.A., Ye, J., Flint, C.L., Farhang-Fallah, J., Dikkes, P., Warot, X.M., Rio, C., Corfas, G., White, M.F., 2003. Insulin receptor substrate-2 deciency impairs brain growth and promotes tau phosphorylation. J. Neurosci. 23, 70847092. Seckl, J.R., Olsson, T., 1995. Glucocorticoid hypersecretion and the age-impaired hippocampus: cause or effect? J. Endocrinol. 145, 201211. Shanley, L.J., Irving, A.J., Harvey, J., 2001. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J. Neurosci. 21, RC186. Shimabukuro, M., Koyama, K., Chen, G., Wang, M.Y., Trieu, F., Lee, Y., Newgard, C.B., Unger, R.H., 1997. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc. Natl. Acad. Sci. USA 94, 46374641. Silverberg, G.D., Miller, M.C., Messier, A.A., Majmudar, S., Machan, J.T., Donahue, J.E., Stopa, E.G., Johanson, C.E., 2010. Amyloid deposition and inux transporter expression at the blood-brain barrier increase in normal aging. J. Neuropathol. Exp. Neurol. 69, 98108. Simons, K., Ikonen, E., 1997. Functional rafts in cell membranes. Nature 387, 569572. Sims, R., Madhere, S., Callender, C., Campbell Jr., A., 2008. Patterns of relationships between cardiovascular disease risk factors and neurocognitive function in African Americans. Ethn. Dis. 18, 471. Skeberdis, V.A., Lan, J., Zheng, X., Zukin, R.S., Bennett, M.V., 2001. Insulin promotes rapid delivery of N-methyl-d-aspartate receptors to the cell surface by exocytosis. Proc. Natl. Acad. Sci. USA 98, 35613566. Skoog, I., Lernfelt, B., Landahl, S., Palmertz, B., Andreasson, L.A., Nilsson, L., Persson, G., Odn, A., Svanborg, A., 1996. A 15-year longitudinal study of blood pressure and dementia. Lancet 347, 11411145. Solfrizzi, V., Panza, F., Colacicco, A.M., DIntrono, A., Capurso, C., Torres, F., Grigoletto, F., Maggi, S., Del Parigi, A., Reiman, E.M., Caselli, R.J., Scafato, E., Farchi, G., Capurso, A., Italian Longitudinal Study on Aging Working Group, 2004. Vascular risk factors; incidence of MCI; and rates of progression to dementia. Neurology 63, 18821891. Solfrizzi, V., Capurso, C., DIntrono, A., Colacicco, A.M., Santamato, A., Ranieri, M., Fiore, P., Capurso, A., Panza, F., 2008. Lifestyle-related factors in predementia and dementia syndromes. Expert Rev. Neurother. 8, 133158. Solfrizzi, V., Scafato, E., Capurso, C., DIntrono, A., Colacicco, A.M., Colacicco, A.M., Frisardi, V., Vendemiale, G., Baldereschi, M., Crepaldi, G., Di Carlo, A., Galluzzo, L., Gandin, C., Inzitari, D., Maggi, S., Capurso, A., Panza, F.; for the Italian Longitudinal Study on Aging Working Group, 2009. Metabolic syndrome, mild cognitive
insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes 48, 18221829. Ott, A., Stolk, R.P., van Harskamp, F., Pols, H.A., Hofman, A., Breteler, M.M., 1999. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 19371942. Ouchi, N., Kihara, S., Funahashi, T., Matsuzawa, Y., Walsh, K., 2003. Obesity, adiponectin and vascular inammatory disease. Curr. Opin. Lipidol. 14, 561566. Panza, F., DIntrono, A., Colacicco, A.M., Basile, A.M., Capurso, C., Kehoe, P.G., Capurso, A., Solfrizzi, V., 2004. Vascular risk and genetics of sporadic late-onset Alzheimers disease. J. Neural. Transm. 111, 6989. Panza, F., DIntrono, A., Colacicco, A.M., Capurso, C., Pichichero, G., Capurso, S.A., Capurso, A., Solfrizzi, V., 2006. Lipid metabolism in cognitive decline and dementia. Brain Res. Rev. 51, 275292. Panza, F., Capurso, C., DIntrono, A., Colacicco, A.M., Frisardi, V., Santamato, A., Ranieri, M., Fiore, P., Vendemiale, G., Seripa, D., Pilotto, A., Capurso, A., Solfrizzi, V., 2008. Vascular risk factors, alcohol intake, and cognitive decline. J. Nutr. Health Aging 12, 376381. Panza, F., Solfrizzi, V., Frisardi, V., Capurso, C., DIntrono, A., Colacicco, A.M., Vendemiale, G., Capurso, A., Imbimbo, B.P., 2009a. Disease-modifying approach to the treatment of Alzheimers disease: from alpha-secretase activators to gammasecretase inhibitors and modulators. Drugs Aging 26, 537555. Panza, F., Capurso, C., DIntrono, A., Colacicco, A.M., Frisardi, V., Lorusso, M., Santamato, A., Seripa, D., Pilotto, A., Scafato, E., Vendemiale, G., Capurso, A., Solfrizzi, V., 2009b. Alcohol drinking, cognitive functions in older age, predementia, and dementia syndromes. J. Alzheimers Dis. 17, 731. Panza, F., Frisardi, V., Capurso, C., Imbimbo, B.P., Vendemiale, G., Santamato, A., DOnofrio, G., Seripa, D., Sancarlo, D., Pilotto. A., Capurso, A., Solfrizzi, V. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J. Alzheimers Dis., in press. Park, L., Zhou, P., Pitstick, R., Capone, C., Anrather, J., Norris, E.H., Younkin, L., Younkin, S., Carlson, G., McEwen, B.S., Iadecola, C., 2008. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein. Proc. Natl. Acad. Sci. USA 105, 13471352. Peila, R., Rodriguez, B.L., White, L.R., Launer, L.J., 2004. Fasting insulin and incident dementia in an elderly population of JapaneseAmerican men. Neurology 63, 228233. Perlmuter, L.C., Nathan, D.M., Goldnger, S.H., Russo, P.A., Yates, J., Larkin, M., 1988. Triglyceride levels affect cognitive function in noninsulin-dependent diabetics. J. Diabet. Complications 2, 210213. Perry, T., Lahiri, D.K., Chen, D., Zhou, J., Shaw, K.T., Egan, J.M., Greig, N.H., 2002a. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor mediated differentiation in PC12 cells. J. Pharmacol. Exp. Ther. 300, 958966. Perry, T., Haughey, N.J., Mattson, M.P., Egan, J.M., Greig, N.H., 2002b. Protection and reversal ofexcitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J. Pharmacol. Exp. Ther. 302, 881888. Perry, T., Lahiri, D.K., Sambamurti, K., Chen, D., Mattson, M.P., Egan, J.M., Greig, N.H., 2003. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels andprotects hippocampal neurons from death induced by Abeta and iron. J. Neurosci. Res. 72, 603612. Peters, R., 2009. The prevention of dementia. Int. J. Geriatr. Psychiatry 24, 452458. Petrovitch, H., White, L.R., Izmirilian, G., Ross, G.W., Havlik, R.J., Markesbery, W., Nelson, J., Davis, D.G., Hardman, J., Foley, D.J., Launer, L.J., 2000. Midlife blood pressure and neuritic plaques, neurobrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia Aging Study. Neurobiol. Aging 21, 5762. Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W.H., Luchsinger, J.A., Wadzinski, B., Duff, K.E., Takashima, A., 2007. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 27, 1363513648. Pi-Sunyer, F.X., 2002. The obesity epidemic: pathophysiology and consequences of obesity. Obes. Res. 10, 97S104S. Qiu, W.Q., Walsh, D.M., Ye, Z., Vekrellis, K., Zhang, J., Podlisny, M.B., Rosner, M.R., Safavi, A., Hersh, L.B., Selkoe, D.J., 1998. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J. Biol. Chem. 273, 3273032738. Qiu, C., von Strauss, E., Fastbom, J., Winblad, B., Fratiglioni, L., 2003. Low blood pressure and risk of dementia in the Kungsholmen project. Arch. Neurol. 60, 223228. Qiu, C., Winblad, B., Fratiglioni, L., 2005. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 4, 487499. Raffaitin, C., Gin, H., Empana, J.P., Helmer, C., Berr, C., Tzourio, C., Portet, F., Dartigues, J.F., Alprovitch, A., Barberger-Gateau, P., 2009. Metabolic syndrome and risk for incident Alzheimers disease or vascular dementia: the Three-City Study. Diabetes Care 32, 169174. Rajala, M.W., Scherer, P.E., 2003. Minireview: the adipocyte at the crossroads of energy homeostasis, inammation, and atherosclerosis. Endocrinology 144, 37653773. Ramasamy, R., Vannucci, S.J., Yan, S.S., Herold, K., Yan, S.F., Schmidt, A.M., 2005. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inammation. Glycobiology 15, 16R28R. Rasouli, N., Molavi, B., Elbein, S.C., Kern, P.A., 2007. Ectopic fat accumulation and metabolic syndrome. Diabetes Obes. Metab. 9, 110. Razay, G., Vreugdenhil, A., Wilcock, G., 2007. The metabolic syndrome and Alzheimer disease. Arch. Neurol. 64, 9396. Reaven, G.M., 1988. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 15951607.
V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417 impairment, and progression to dementia. The Italian Longitudinal Study on Aging. Neurobiol. Aging; doi:10.1016/j.neurobiolaging.2009.12.012. Solfrizzi, V., Frisardi, V., Capurso, C., DIntrono, A., Colacicco, A.M., Vendemiale, G., Capurso, A., Panza, F., 2010a. Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms. Ageing Res. Rev. 9, 184199. Solfrizzi, V., Scafato, E., Capurso, C., DIntrono, A., Colacicco, A.M., Frisardi, V., Vendemiale, G., Baldereschi, M., Crepaldi, G., Di Carlo, A., Galluzzo, L., Gandin, C., Inzitari, D., Maggi, S., Capurso, A., Panza, F., 2010b. Metabolic syndrome and the risk of vascular dementia. The Italian Longitudinal Study on Aging. J. Neurol. Neurosurg. Psychiatry 81, 433440. Sondag, C.M., Combs, C.K., 2006. Amyloid precursor protein cross-linking stimulates beta amyloid production and pro-inammatory cytokine release in monocytic lineage cells. J. Neurochem. 97, 449461. Stewart, R., Masaki, K., Xue, Q.L., Peila, R., Petrovitch, H., White, L.R., Launer, L.J., 2005. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study. Arch. Neurol. 62, 5560. Stewart, R., Xue, Q.L., Masaki, K., Petrovitch, H., Ross, G.W., White, L.R., Launer, L.J., 2009. Change in blood pressure and incident dementia: a 32-year prospective study. Hypertension 54, 233240. Stranahan, A.M., Arumugam, T.V., Cutler, R.G., Lee, K., Egan, J.M., Mattson, M.P., 2008. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat. Neurosci. 11, 309317. Stranahan, A.M., Zhou, Y., Martin, B., Maudsley, S., 2009. Pharmacomimetics of exercise: novel approaches for hippocampally-targeted neuroprotective agents. Curr. Med. Chem. 16, 46684678. Swan, G., Lessov-Schlaggar, C., 2007. The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychol. Rev. 17, 259273. Udagawa, J., Hashimoto, R., Hioki, K., Otani, H., 2006. The role of leptin in the development of the cortical neuron in mouse embryos. Brain Res. 1120, 7482. Tan, Z.S., Seshadri, S., Beiser, A., Wilson, P.W., Kiel, D.P., Tocco, M., DAgostino, R.B., Wolf, P.A., 2003. Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Arch. Intern. Med. 163, 10531057. Tervo, S., Kivipelto, M., Hnninen, T., Vanhanen, M., Hallikainen, M., Mannermaa, A., Soininen, H., 2004. Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects. Dement. Geriatr. Cogn. Disord. 17, 196203. Trayhurn, P., Wood, I.S., 2005. Signalling role of adipose tissue: adipokines and inammation in obesity. Biochem. Soc. Trans. 33, 10781081. Tzourio, C., Dufouil, C., Ducimetire, P., Alprovitch, A., 1999. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA Study Group. Epidemiology of vascular aging. Neurology 53, 19481952. van den Berg, E., Biessels, G.J., de Craen, A.J., Gussekloo, J., Westendorp, R.G., 2007. The metabolic syndrome is associated with decelerated cognitive decline in the oldest old. Neurology 69, 979985. van Dijk, G., Buwalda, B., 2008. Neurobiology of the metabolic syndrome: an allostatic perspective. Eur. J. Pharmacol. 585, 137146. van Exel, E., de Craen, A.J., Gussekloo, J., Houx, P., Bootsma-van der Wiel, A., MacFarlane, P.W., Blauw, G.J., Westendorp, R.G., 2002. Association between high-density lipoprotein and cognitive impairment in the oldest old. Ann. Neurol. 51, 716721. van Vliet, P., van de Water, W., de Craen, A.J.M., Westendorp, R.G.J., 2009. The inuence of age on the association between cholesterol and cognitive function. Exp. Gerontol. 44, 112122. Vanhanen, M., Koivisto, K., Kuusisto, J., Mykkanen, L., Helkala, E.L., Hanninen, T., Riekkinen Sr., P., Soininen, H., Laakso, M., 1998. Cognitive function in an elderly population with persistent impaired glucose tolerance. Diabetes Care 21, 398402. Vanhanen, M., Koivisto, K., Moilanen, L., Helkala, E.L., Hnninen, T., Soininen, H., Kervinen, K., Kesniemi, Y.A., Laakso, M., Kuusisto, J., 2006. Association of metabolic syndrome with Alzheimer disease: a population-based study. Neurology 67, 843847. Veglio, F., Paglieri, C., Rabbia, F., Bisbocci, D., Bergui, M., Cerrato, P., 2009. Hypertension and cerebrovascular damage. Atherosclerosis 205, 331341. Wang, S.Y., 2002. Weight loss and metabolic changes in dementia. J. Nutr. Health Aging 6, 201205.
417
Wang, L., Sapuri-Butti, A.R., Aung, H.H., Parikh, A.N., Rutledge, J.C., 2008. Triglyceriderich lipoprotein lipolysis increases aggregation of endothelial cell membrane microdomains and produces reactive oxygen species. Am. J. Physiol. Heart Circ. Physiol. 295, H237H244. Wang, L.Y., Larson, E.B., Sonnen, J.A., Shofer, J.B., McCormick, W., Bowen, J.D., Montine, T.J., Li, G., 2009. Blood pressure and brain injury in older adults: ndings from a community-based autopsy study. J. Am. Geriatr. Soc. 57, 19751981. Watson, G.S., Craft, S., 2003. The role of insulin resistance in the pathogenesis of Alzheimers disease: implications for treatment. CNS Drugs 17, 2745. Wayner, M.J., Armstrong, D.L., Phelix, C.F., Oomura, Y., 2004. Orexin-A(Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 25, 991996. Weng, Z., Signore, A.P., Gao, Y., Wang, S., Zhang, F., Hastings, T., Yin, X.M., Chen, J., 2007. Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. J. Biol. Chem. 282, 3447934491. White, H., Pieper, C., Schmader, K., Fillenbaum, G., 1996. Weight change in Alzheimers disease. J. Am. Geriatr. Soc. 44, 265272. Whitmer, R.A., Gunderson, E.P., Barrett-Connor, E., Quesenberry Jr., C.P., Yaffe, K., 2005. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 330, 1360. Whitmer, R.A., Gustafson, D.R., Barrett-Connor, E., Haan, M.N., Gunderson, E.P., Yaffe, K., 2008. Central obesity and increased risk of dementia more than three decades later. Neurology 71, 10571064. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Van Bronswijk, W., Martins, R., 2002. Alzheimers beta-amyloid peptides compete for insulin binding to the insulin receptor. J. Neurosci. 22, RC221. Xu, W.L., Qiu, C.X., Wahlin, A., Winblad, B., Fratiglioni, L., 2004. Diabetes mellitus and risk of dementia in the Kungsholmen project: a 6 year follow-up study. Neurology 63, 11811186. Yaffe, K., Barrett-Connor, E., Lin, F., Grady, D., 2002. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch. Neurol. 59, 378384. Yaffe, K., Kanaya, A., Lindquist, K., Simonsick, E.M., Harris, T., Shorr, R.I., Tylavsky, F.A., Newman, A.B., 2004a. The metabolic syndrome, inammation, and risk of cognitive decline. JAMA 292, 22372242. Yaffe, K., Blackwell, T., Kanaya, A.M., Davidowitz, N., Barrett-Connor, E., Krueger, K., 2004b. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 63, 658663. Yaffe, K., Haan, M., Blackwell, T., Cherkasova, E., Whitmer, R.A., West, N., 2007. Metabolic syndrome and cognitive decline in elderly Latinos: ndings from the sacramento area Latino study of aging study. J. Am. Geriatr. Soc. 55, 758762. Yaffe, K., Weston, A.L., Blackwell, T., Krueger, K.A., 2009. The metabolic syndrome and development of cognitive impairment among older women. Arch. Neurol. 66, 324328. Yan, S.D., Bierhaus, A., Nawroth, P.P., Stern, D.M., 2009. RAGE and Alzheimers disease: a progression factor for amyloid-beta-induced cellular perturbation? J. Alzheimers Dis. 16, 833843. Zhang, Y., Scarpace, P.J., 2006. The role of leptin in leptin resistance and obesity. Physiol. Behav. 88, 249256. Zhang, F., Wang, S., Signore, A.P., Chen, J., 2007. Neuroprotective effects of leptin against ischemic injury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke 38, 23292336. Zhang, F., Chen, J., 2008. Leptin protects hippocampal CA1 neurons against ischemic injury. J. Neurochem. 107, 578587. Zhang, T., Pan, B.S., Zhao, B., Zhang, L.M., Huang, Y.L., Sun, F.Y., 2009. Exacerbation of poststroke dementia by type 2 diabetes is associated with synergistic increases of beta-secretase activation and beta-amyloid generation in rat brains. Neuroscience 161, 10451056. Zhao, Y., Ye, W., Boye, K.S., Holcombe, J.H., Hall, J.A., Swindle, R., 2010. Prevalence of other diabetes-associated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy. J. Diabetes Complications 24 (1), 919. Zlokovic, B.V., 1996. Cerebrovascular transport of Alzheimers amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci. 59, 14831497. Zuliani, G., Ble, A., Zanca, R., Munari, M.R., Zurlo, A., Vavalle, C., Atti, A.R., Fellin, R., 2001. Lipoprotein prole in older patients with vascular dementia and Alzheimers disease. BMC Geriatr. 1, 5.

Metabolic A and Alzheimer Disease

Enviado por

Dados do documento

Descrição original:

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Metabolic A and Alzheimer Disease

Enviado por

Direitos autorais:

Formatos disponíveis

Ageing Research Reviews 9 (2010) 399417

Contents lists available at ScienceDirect

Ageing Research Reviews

Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimers disease

Article history: Received 21 April 2010 Accepted 23 April 2010

V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417

V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417

Longitudinal, population-based (8 years)

3646 individuals aged 65 years or older

Longitudinal, population-based (32 years)

1890 men (aged 7798 years)

Incident diagnosis of dementia

Longitudinal, population-based (21 years)

1449 individuals aged 6579 years

Incident diagnosis of dementia and AD

Longitudinal, population-based (27 years)

10,276 subjects, mean age: 74.5 years

Incident diagnosis of dementia

Longitudinal, population-based (36 years)

6583 subjects, 7387 years of age

Incident diagnosis of dementia

Longitudinal, population-based (18 years)

Incident diagnosis of dementia and AD

Longitudinal, population-based (5 years)

Incident diagnosis of dementia and AD

Longitudinal, population-based (5.4 years)

2798 adults without dementia (mean age:74.7 years)

Incident diagnosis of dementia, AD, and VaD

Longitudinal, population-based (4 years)

7027 osteoporotic postmenopausal women (mean age, 66.3 years)

Longitudinal, population-based (4 years)

999 white men and women aged 4289 years

Three cognitive tests (MMSE, VF test, and TMT-B) were measured

2374 participants (7078 years of age)

Gregg et al. (2000) Study of Osteoporotic Fractures Research Group USA

Longitudinal, population-based (36 years)

Community-dwelling white women 65 years and older (n = 9679)

Vanhanen et al. (1998) The Kuopio Study Finland

Longitudinal, population-based (3.5 years)

1300 older subjects, (mean age: 73.2 years)

Longitudinal, population-based (4 years)

1389 older subjects, aged 5971 years

Longitudinal, population-based (4.3 years)

1262 elderly subjects without dementia (mean age: 76.5 years)

Incident AD and dementia associated with stroke

Longitudinal, population-based (5 years)

5574 older subjects, aged 65 years and older

Incident dementia (including AD and vascular cognitive impairment)

Longitudinal, population-based (4.3 years)

918 subjects, aged 65 years and older

Incident all-cause MCI, aMCI, and naMCI

Longitudinal, population-based (2.1 years)

6370 subjects, aged 65 years and older

Incident diagnosis of dementia, AD, and VaD

Longitudinal, population-based (15 years)

A cohort of 1455 persons with T2DM, aged 5971 years

Incident diagnosis of dementia and AD

Longitudinal, population-based (6 years)

1301 community dwellers aged 75 years and older

Incident diagnosis of dementia, AD, and VaD

V. Frisardi et al. / Ageing Research Reviews 9 (2010) 399417

Longitudinal, population-based (5.5 years)

1138 individuals without dementia at baseline (mean age = 76.2 years)