Dementia

Dementia Dementiahas become an each(prenominal)-important sicknessbecause the population is aging rapidly and the cost of health c be associated with insanityis of all time increasing. In extension to cognitive swear out hindrance, associated behavioral and psychological symptoms of frenzy(BPSD) worsen patients tint of life and increase c begivers charge.Alzheimers unhealthinessis the most common type of insanityand both behavioral disturbance and cognitive constipation ofAlzheimers infirmity argon thought to be associated with the N-methyl-D-aspartate (NMDA) dysfunction as increasing evidence of dys utilitarian glutamatergic neurotransmission had been reported in behavioral reassigns and cognitive settle inAlzheimers disorder. Wereviewthe literature regarding monomania(especi every(prenominal)yAlzheimersdisease), BPSD and relevant findings on glutamatergic and NMDA neurotransmission, including the sums of memantine, a NMDA sensory receptor antagonist, and NMDA-enhanci ng agents, such as D-serine and D-cycloserine.Literatures suggest that behavioral disturbance and cognitive impairment ofAlzheimersdisease whitethorn be associated with excitatory neurotoxic effects which result in impairment of nervous plasticity and chronic processes. Memantine shows benefits in improving cognition, function, agitation/aggression and delusion inAlzheimersdisease. On the another(prenominal) hand, whatever NMDA modulators which bring up NMDA function through the co-agonist spinal column site can too correct cognitive function and psycho symptoms.We propose that modulating NMDA neurotransmission is effective in treating behavioral and psychological symptoms ofAlzheimersdisease. Prospective see using NMDA enhancers in patients withAlzheimersdiseaseand associated behavioral disturbance is needed to verify this hypothesis. Mental disorders constitute a huge sociable and economic burden for health care systems world astray 1, raising the question of effective a nd lasting treatments. Physical performance (PA) and ferment (EX) continue to gain the attention of practitioners and interrogationers with regard to prevention and treatment of different psychopathological abnormalities.In the general population, several(prenominal)(prenominal) epidemiological studies curb plant significant cross-sectional correlations surrounded by mental health and PA levels. In an adult US population, regular PA is associated with a significantly slumpd prevalence of current major depression, panic disorder, agoraphobia, tender phobia, and specific phobia 2. A submit from Norway confirmed this negative cross-sectional k straightwayledge among depression and unfilled-time PA of any intensity (not work- plug intod PA), and pointed out that social agentive roles such as social support, rather than biological markers, play an important role 3.Recently, a Dutch study replicated this finding, reporting lour rates of any affective, anxiety, or substance use disorder in subjects who consummationd at least 1 h/wk, without finding a linear dose-response relationship 4. Prospectively, the all overall relative relative incidence of mental disorders and co-morbid mental disorders, as head as the incidence of anxiety, somato direct, and dysthymic disorder, decreases by PA 5. Furtherto a greater extent, a four-year prospective study revealed that PA decreases the incidence rates of depressive and anxiety disorders in sr. adults 6.Finally, ten Have et al. reported in their epidemiological study that patients engaging in regular PA were more likely to recover from their mental illness at a tierce-year follow-up In psychiatric patients, different mechanisms of action for PA and EX take away been discussed On a neurochemical and physiological level, a number of subacute changes occur during and following bouts of EX, and several long-term adaptations are re new-maded to regular EX information.For instance, EX has been found to norma lize reduced levels of mind-set-derived neurotrophic factor (BDNF) and at that placefore has neuro restrictive or even neurotrophic effects 7-9. Animal studies found EX-induce changes in different neurotransmitters such as serotonin and endorphins 10,11, which relate to mood, and confirmative effects of EX on stress re bodily function (e. g. , the hypothalamus-pituitary-adrenal axis 12,13). Finally, anxiolytic effects of EX mediated by atrial natriuretic peptide construct been reported 14.Potential psychological mechanisms of action acknowledge schooling and extinction, changes in body scheme and health attitudes/behaviors, social reinforcement, experience of checky, shift of external to more upcountry locus of control, ameliorate coping strategies, or simple distraction Several prospective studies earn found that a high level of PA seems to delay the onset of dementia (see 74 for a review). Since improvements in dominance and endurance after training were found in cognit ively impaired patients as good as healthy controls 75, PA interventions are generally feasible in this population.For Alzheimers disease (AD), preliminary evidence suggests that EX interventions whitethorn improve communication performance 78, Mini Mental State Examination scores and vocal fluency 79, and disruptive behavior 80. Four studies 81-84 found that PA shadowyed down and partially reversed the resist in performance of activities of daily living and progression of the cognitive symptoms related to dementia, in contrast to an older study, which did not find improvements in functional ability 85. Zschucke , E. and Gaudlitz, K.Exercise and Physical Activity in Mental Disorders clinical and Experimental Evidence Zschucke , E. and Gaudlitz, K. (2013) Exercise and Physical Activity in Mental Disorders Clinical and Experimental Evidence. daybook of Preventative Medicine and Public Health, 46 (1), p. 12-21. Available at http//www. ncbi. nlm. nih. gov/pmc/articles/PMC3567313/ A ccessed 6th Mar 13. Leptin, an adipocytokine produced in the peripheral system as wholesome as in the brain, is implicated in obesity, food intake, glucose homeostasis, and efficacy expenditure.Leptin reflectivity levels and signalise nerve pamphlets may as come up be linked to the pathophysiology of neurodegenerative diseases including Alzheimers disease. Epidemiological studies extradite demo that higher(prenominal) go around leptin levels are associated with lower attempt of dementia including Alzheimers disease, and lower circulating levels of leptin have been reported in patients with Alzheimers disease. Leptin receptors are highly expressed in the genus Hippocampus, a brain field of study refer in acquirement and retrospect and severely affected during the course of Alzheimers disease.In laboratory studies, several in vivo and in vitro studies have shown that leptin supplementation decreases starchlike-? (A? ) mathematical product and tau phosphorylation, twai n major biochemical events that play a cardinal role in the pathogenesis of Alzheimers disease. In this review, we leave alone review the social organization of leptin, the type of receptors of leptin in the brain, the various biological functions attributed to this adipocytokine, the signalize channels that govern leptin actions, and the potential role of leptin in the pathophysiology of Alzheimers disease.Leptin exerts its functions by binding to the leptin receptor (ObR). This binding can involve several foretoken paths including JAK/STAT channel, ERK pathway and the PI3K/Akt/mTOR Pathway. Modulation of these pathways leads to the polity of a multitude of functions that define the intricate involvement of leptin in various physiological tasks. In this review, we will specifically relate the potential involvement of leptin augury in Alzheimers disease based on work published by several laboratories including ours.All this work points to leptin as a possible direct for o ntogeny supplementation therapies for reducing the progression of Alzheimers disease. Leptin is a 146 aminic acid protein with a molecular tilt of 16 kDa encoded by theobgene and in the beginning, but not exclusively, expressed by the white fat wind (WAT) and is implicated in obesity, food intake, and muscle homeostasis. Leptin protein was discovered by the molecular geneticist Jeffrey Friedman in 1994 at Rockefeller University and the work was published in a landmarkNaturepaper in December 1994 1.The mankindobgene has been mapped to chromosome 7q31. 3 2 and encodes a 4. 5 kb messenger RNA transcript that is translated into a 167 amino group acid peptide and subsequently processed in the ER into the 146 amino acid mature leptin protein 1. Antecedent to the discovery of the leptin protein and positional cloning of theobgene in 1994, theob/ob setback characterized by hyperphagia and a mark obese phenotype was serendipitously discovered by animal caretakers in 1950 at Jackson Laboratories 3.It was the general consensus that theob/obmouse possessed a mutation in theobgene, but this was not elucidated and unequivocally constituted until the discovery of the leptin protein and mapping of theobgene by Friedman and colleagues in 1994 who showed that the mutation resulted in the personnel casualty of leptin production. In 1966, thedb/dbmouse was discovered, again at Jackson Laboratories, which not only exhibited a standardized hyperphagic, obese phenotype, but excessively hyperglycemia 4.Tartaglia and colleagues in 1995 showed that thedb/dbmouse phenotype can be attributed to the mutation in thedbgene that codes for the long-form of the leptin receptor obRb 5. However, it was the seminal work of Doug Coleman and colleagues who demonstrate by a series of parabiosis experiments usingob/obmice anddb/dbmice pairs and established that theob/obmice lacked a circulating factor whereas thedb/dbmice produced the circulating factor but were not able to resolve to i t 6,7.The validity of these breakthroughs was affirmed by subsequent discovery of the leptin protein and cloning of theobgene 1 as closely as the cloning of thedbgene which coded for the long-form leptin receptor obRb 5. Further corroboration emanated from the finding that thedbmice produced the cut form of obRb that was incapable of transducing leptin-mediated intra jail cellular signal transduction 8-12 and institution of exogenous leptin obviated the obese, hyperphagic, hypothermic, and hypometabolic phenotype inob/obmice 13-15. Go to -Leptin structure, expression, and secretion The crystal structure of leptin has revealed the secondary and tertiary structure of the leptin molecule. The three dimensional crystal structure of leptin depicts the presence of four anti parallel of latitude ? -helices (A, B, C, and D) 16. Two long crossover loops connect the A-B and C-D ? -helices, while a unequal loop connects the B-C ? -helices 16. The entire leptin molecule is oblong shaped w ith the dimensions of 20x25x45 A016. The entire molecule comprising of the roll of four ? -helical loops adopts a bilayered stratified structure with ? helices A-D in one layer contiguous with ? -helices B-C in the other layer 16. The phase adopted by the leptin molecule results in the surface emergence of a few key hydrophobic resi cods like Phe41, Phe92, Trp100, Trp138, and Leu142which not only play an indispensable role in the regulation of solubility and assembly kinetics of the leptin protein, but are besides critically requisite for as headspring as play the binding of leptin to the leptin receptor and determine the binding kinetics of the leptin-leptin receptor interaction 16.The three dimensional four-helical bundle crystal structure of leptin exhibits an overt, conspicuous congruence with other cytokines such as growth hormone (GH) 17, leukemia repressive factor (LIF) 18, and G-CSF (G-colony stimulating factor) 19, despite lack of primary sequence homology with these proteins or other proteins 1. Leptin is expressed primarily by the white adipose create from raw stuff 1,20 and circulating leptin levels are proportional to the white adipose tissue mass 21,22. In mans, leptin expression in the subcutaneous adipose tissue is significantly more in magnitude than omental adipose tissue 23-26.Other studies have exhibit no difference in leptin expression between the subcutaneous and omental adipose tissue 27. Leptin expression in humans alike exhibits sexual dimorphism with circulating leptin levels nearly 3-fold greater in females than males 25,28,29. It is now certain that other tissues in addition produce leptin, including stomach 30,31, mammary secreter 32, human placenta 33, ovaries 34, heart 35, skeletal muscle 36, pituitary gland 37, and the brain 37-39. In the brain leptin mRNA expression and immunoreactivity has been seen in the hypothalamus, cortex, dentate convolution and the hippocampus of the rat 38,39.Leptin immunoreactivity has to a fault been reported in the mouse and hamster brain 40. Leptin expression and circulating leptin levels are primarily possible on the white adipose tissue mass 21,22 and are significantly elevated in obesity 21,22,41,42. Consistent with this observation, weight loss is associated with a decrease in leptin levels in the plasma 22. Leptin levels in the plasma likewise fluctuate in an ultradian trend and exhibit diurnal rhythm 43,44. Leptin secretion occurs in a pulsatile rhythm with 30 pulses of leptin secretion in a 24-hour cycle 43,45.Acute caloric restriction reduces leptin levels by 30% in spite of sort 24 hours 46-48 whereas caloric trim elevates leptin levels in the plasma by 35% within 5-8 hours 47. Therefore, nutritional intake consecrates leptin expression in an acute as well as chronic fashion. The physiological and hormonal parameters that increase leptin expression include obesity 21,22,41, overfeeding or excess caloric intake 49,50, insulin 51-55, glucocorticoi ds 51,52,56,57, glucose 58, tumor necrosis factor ? (TNF? ) 54,59, estradiol 60-62, and IL1 63,64 among others.The physiological and hormonal factors that decrease leptin expression include androgens 61,65, acute caloric restriction 49,50, growth hormone 66-69, somatostatin 68,70, mental picture to cold temperatures 50,71,72, ? 3adrenergic agonists 70,73-76, long-term exercise 77,78, cAMP (51, 57), PPAR? agonists such as thizolidinediones Pioglitazone, Troglitazone, and Rosiglitazone 79, and free fat person acids 80 among others. Go to - Leptin receptors Leptin receptors (obR) are encoded by thedbgene 5.The obR are transmembrane spanning proteins that transduce and mediate leptin signalize. The obR exhibit structural and functional homology to the class I cytokine receptors 81,82. The obR along with other class I cytokine receptors are typified by the lineament presence of four cysteine residues and a WSXWS motif 81,83 which are a part of multiple fibronectin Type deuce-ace su bdomains in their extracellular domains 84. The obR transcript undergoes alternate splicing to generate six different receptor isoforms (obRa ob-Rf) 11.The six isoforms of obR are distinguished by and exhibit very little homology in their intracellular domain 85. However, all the six isoforms have the like extracellular domain of over 800 amino acids and a transmembrane domain that spans 34 amino acid residues 85. The six isoforms of obR are pigeonholed into three different groups, namely absolutely form, long form, and secreted obR 85. The bypass-form of obR subsuming obRa (894 amino acids), obRc (892 amino acids), obRd (901 amino acids), and obRf (896 amino acids) possess a short 30-40 amino acid residue intracellular domain 85. bRb (1162 amino acids) is the only functionally active leptin receptor isoform capable of transducing leptin mansion as it contains an intracellular domain that spans 280 amino acid residues 5. The obRe isoform (805 amino acids) lacks the intracellul ar domain and is in that locationfore classified as a secreted soluble receptor and functions as a buffering system involved in the transport of leptin and bioavailibility of free circulating leptin 86,87.The short isoforms obRa, obRc, obRd, and obRf are extravagantly expressed in the choroid plexus and endothelial cells of the brain microvasculature that form the BBB and may therefore gravel the flux of leptin crosswise the BBB 88,89. obRb is pervasively expressed in the human and gnawer brain with the highest density in the ventromedial, arcuate, and dorsomedial hypothalamic nuclei 90-93. obRb is termed the long-form leptin receptor and is solely responsible for propagating signal transduction mechanisms initiated by leptin 5,94.The short forms of the leptin receptor ob-Ra, ob-Rc, obRd, and obRf are devoid of intracellular signaling motifs that are obligatory for signal transduction 5. However the short form receptors obRa and obRc are highly expressed in the choroid plexus an d it is speculated that they mediate the uptake of leptin across the BBB (88, 89). obRb expression has been reported in several regions of the rodent and human brain including the hypothalamus 90,92,93, hippocampus, brain stem (nucleus of the lone(a) tract and the dorsal motor nucleus of the vagus), amygdala and the substantia nigra 92,93,95,96.In the hippocampus leptin receptor immunoreactivity is observed in the CA1/ CA3 region and the dentate gyrus 95,97. Furthermore, axonal and somato-dendritic regions and hippocampal synapses exhibit leptin receptor immunolabeling in primary hippocampal cultures 97. Go to - biological and physiological functions Leptin was discovered as the endogenous hormone that precludes obesity and regulates aught homeostasis 1.Antecedent to the discovery of leptin in 1994, intimately twain decades ago, Doug Coleman had posited the role of a circulating hormone that thwarted obesity via its action in the brain to regulate food intake and energy homeosta sis and in the peripheral tissues to regulate energy catabolism, thermogenesis as well as basal metabolism 7. This was corroborated in the mid 1990s after the discovery of leptin by studies that demonstrated in rodents that administration of exogenous leptin decreased food intake and augmented energy expenditure 13-15,98,99.Leptin administration augments energy expenditure by spark the ? -oxidation of fatty acids in the mitochondria and besides inducing the expression of enzymes involved in ? -oxidation 100. However, the notion that high levels of leptin augment weight loss and circumvent obesity must be tempered with the fact that high endogenous leptin levels have been effete in thwarting obesity in humans and other mammals 21,22,41. This can be ascribed to a phenomenon termed leptin resistance 101-103. Leptin plays a pivotal role in the induction of puberty and fertility.Leptin reinstates puberty, restores fertility inob/obmice, escalates puberty and fosters reproductive behavi or in wildtype rodents 104-107. Leptin directly regulates the hypothalamic-pituitary-gonadal (HPG) axis by inducing gonadotropin release and modulating estradiol production in the ovarian follicles 108,109. Leptin also regulates the hypothalamic-pituitary-adrenal (HPA) axis by attenuating corticotrophin releasing hormone (CRH) production and release 110,111 as well as directly inhibiting ACTH (adrenocorticotropic hormone)-induce glucocorticoid release from the adrenal cortex 111-113.Leptin is also integrally involved in the physiological homeostasis of the circulatory system. Emerging evidence implicates leptin in hematopoeisis as leptin is involved in proliferation and differentiation haematogenic forerunners 114-116. Higher plasma levels of leptin (100ng/mL), suchas those observed in obese somebodys, foster and promote platelet aggregation 117. Leptin is also one of the most potent inducers of vascular epithelial cell growth and angiogenesis and the short forms and the long-form of the leptin receptor is abundantly expressed in the vasculature 117-119.Go to - Leptin function in the brain Hypothalamus Leptin signaling in the hypothalamus regulates food intake and energy homeostasis in mammals. The arcuate nucleus (ARC), dorsomedial nucleus (DMH), and the ventromedial nucleus (VMH) of the hypothalamus express the obRb in the greatest density. In the ARC, the obRb is abundantly expressed in two disparate nervous cell types, ones that express neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the others that express pro-opiomelanocortin (POMC) 92,120-122.Leptin induced energizing of the obRb in the POMC neurons results in depolarization and increase biosynthesis of ? -melanocyte-stimulating hormone (? -MSH) which signals downstream by actuating the melanocortin system comprising of melanocortin-3-receptors (MC3R) and melanocortin-4-receptors (MC4R) expressed by the second order neurons downstream to evoke an anorexiogenic (decreased appetite) respons e 122-127. Activation of the melanocortin pathway not only suppresses appetite but also increases energy expenditure by increasing pitying tone resulting in ? oxidation of fatty acids in skeletal and adipose tissue. While leptin instigates the POMC-expressing neurons, the actuation of obRb by leptin in the NPY/AgRP neurons results in the decreased genesis of NPY and AgRP peptides which are orexiogenic (increase appetite) in personality 122,128. Therefore, in conspectus, leptin signaling in the hypothalamus results in the decreased expression of orexiogenic peptides (NPY, AgRP) and change magnitude expression of anorexiogenic peptides (? -MSH) as well as increased energy expenditure in the adipose tissue and skeletal muscle tissue.Hippocampus Leptin receptors are abundantly expressed in the CA1 and CA3 regions of the hippocampus as well as the dentate gyrus 95,97. Leptin regulates the excitability and inflaming of hippocampal neurons via the modulation of BK potassium channels 9 7. Leptin also improves store process and retention when administered directly into the CA1 region in mice 129 and rodents that are deficient in the leptin receptor (db/dbmice andfa/farats) exhibit profound deficits in spatial learning and memory 129-131.Treatment of acute hippocampal slices with leptin results in the passage of short-term potentiation (STP) to long term potentiation (LTP) by enhancing Ca2+influx through NMDA receptors 132. Leptin increases synaptogenesis and support in memory formation in the hippocampus and is purported to be a cognitive enhancer 133. Leptin also increases neurogenesis in the dentate gyrus of adult mice 134. Leptin also plays a critical role in hippocampal neuronal endurance by activating the PI3K-Akt and JAK2/STAT3 signal transduction pathways 135.Leptin upregulates the expression of potent endogenous antioxidant enzyme Mn-SOD (manganese superoxide dismutase) and the anti-apoptotic protein Bcl-xL (B-cell lymphoma xL) in a STAT3-dependent mann er in the hippocampus 135. Leptin stabilizes mitochondrial membrane potential and attenuates the glutamate-induced mitigation in mitochondrial membrane potential and also extenuates the free iron-induced augmentation in mitochondrial ROS 135. Go to - Leptin signalingLeptin binding to its long-form receptor obRb actuates four major signal transduction pathways that are twin to obRb JAK/STAT pathway, ERK pathway, PI3K/Akt/mTOR pathway, as well as the AMPK/SIRT1 signal transduction pathways. JAK/STAT pathway Leptin signaling via the obRb is integrally conjugated to the JAK2/STAT3, JAK2/STAT5 and JAK2/STAT6 pathways 10. The long-form of the leptin receptor obRb is constitutively coupled to Janus kinase 2 (JAK2) via the evolutionary conserved domains proximal to the membrane 136.The binding of leptin to obRb evokes a conformational change in the receptor that actuates JAK2 by phosphorylation at Tyr1007/1008residues 136. Activated phosphorylated JAK2 subsequently phosphorylates evoluti onary conserved tyrosine residues of obRb 94 at Tyr985, Tyr1077and Tyr1138137,138. The obRb phosphorylated at Tyr1077and Tyr1138serves as a docking site and recruits Srchomology 2 (SH2)- and Src-homology 3 (SH3)-domain comprising roteins that subsume proteins such as aim Transducer and Activator of Transcription 3 (STAT3), Signal Transducer and Activator of Transcription 5 (STAT5), and Src homology region 2 domain-containing phosphatase 2 (SHP2) 139. The phosphorylated Tyr1138residue of obRb recruits STAT3 and STAT5 which are subsequently phosphorylated by JAK2 at Tyr705and Tyr694respectively. The phosphorylation STAT3 and STAT5 causes their disengagement from the leptin receptor, results in the dimerization of STAT proteins via their phosphotyrosine residues in the SH2 domains 140-142, and culminates in their nuclear translocation 142.In the nucleus, STAT dimers bind to manifest motifs or elements in the DNA called ? -IFN-activated site (GAS) in the enhancer regions of target gen es and thereby modulate and regulate gene expression of target genes 142-146. In the nucleus, the STAT signaling is abrogated by dephosphorylation and subsequent export of STAT proteins from the nucleus to the cytosol 142,144,147 or by targeted degradation of the STAT proteins via the Ubiquitin Proteasomal System (UPS) 148.The JAK/STAT pathway is negatively regulated by three classes of proteins, namely suppressors of cytokine signaling (SOCS), protein inhibitors of activated STATs (PIAS), and protein tyrosine phosphatases (PTP) 149. There are eight members of the SOCS family and their expression is induced by JAK/STAT signaling (STAT3 in particular) thereby suggesting the knowence of a negative feedback loop that abrogates JAK/STAT signaling 150.The SOCS proteins negatively regulate the JAK/STAT pathway by competitively engaging and occupying the phosphotyrosine residues in obRb via their SH2 domains and obviating the recruitment of STAT proteins to obRb, thereby precluding STAT activating 150,151. SOCS proteins via their SH2 domains also directly bind to JAK2 and extenuate the kinase activity of JAK2 150,151. The PIAS proteins negatively regulate the JAK/STAT signaling pathway by impeding the binding of STAT proteins to the response elements in the DNA by somaticly interacting and binding with STAT proteins via their zinc-binding RING-finger domains 151.SHP1 and SHP2 are most well characterized protein tyrosine phosphatases implicated in the negative regulation of the JAK/STAT pathway 149. SHP1 and SHP2 possess two SH2 domains and therefore bind to phosphotyrosines of JAK2 and obRb and effectuate the dephosphorylation of JAK2 and obRb thereby terminating the JAK/STAT signaling 149. ERK pathway The extracellular regulated kinase (ERK) pathway is an integral part of a larger signaling network called mitogen activated protein kinase (MAPK) pathway that is activated by leptin signaling via the leptin receptor (obRb).While phosphorylation of Tyr1138and Tyr10 77are both requisite and mediate the activation of STAT3 and STAT5 respectively, the phosphorylation of Tyr985of obRb mediates the activation of ERK pathway 138. Leptin signaling via the obRb evokes the actuation of ERK pathway, both centrally and peripherally, as well as inin vivoandin vitro experimental paradigms 85. Leptin evokes the activation of ERK pathway by both JAK2-mediated and JAK2-independent signaling effects 94,152.Contemporary evidence has implicated the protein tyrosine phosphatase SHP2 and the adaptor protein Grb2 (growth receptor bound 2) as the requisite mediators in the leptin-induced activation of ERK signaling pathway 153. Leptin signaling also activates other members and signaling cascades subsumed under the MAPK signaling pathway, namely p38 154-157 and JNK pathways 156. PI3K/Akt/mTOR pathway Leptin signaling also induces the activation of the ubiquitous, pervasive, nutrient-sensitive anabolic, and the broad spectrum PI3K/Akt/mTOR pathway 152,158-161.Empiric al evidence has demonstrated that the adaptor proteins IRS1 (insulin receptor substrate 1) and IRS2 (insulin receptor substrate 2) mediate the leptin-obRb induced activation of PI3K-Akt pathway 94,158,162. A multitude of studies have demonstrated that leptin induces the activation of Akt via phosphorylation of Akt at Ser473163,164. As a consequence, Akt activation is ensued upon leptin signaling which results in inhibition of GSK3? through phosphorylation at Ser9residue 165-167.Evidently leptin also activates the serine/threonine kinase mammalian target of Rapamycin (mTOR) in the hypothalamus and macrophages 168,169 through the PI3K-Akt pathway 170. mTOR is an evolutionary conserved kinase that modulates translation of several mRNA transcripts involved in cell growth and proliferation. mTOR regulates translation by phosphorylation and fading of the inhibitor of mRNA translation, eukaryotic initiation factor 4E-binding protein (4E-BP) 171-175, as well as through the phosphorylation and activation of S6 kinase (p70S6K1) 176,177. TOR is autophosphorylated at Ser2481and exhibits spontaneous intrinsic kinase activity under the activation of Akt 178,179. mTOR phosphorylation and activation is negatively regulated by the TSC1/TSC2 protein complex 170. Akt phosphorylates TSC2 causing disintegration of the TSC1/TSC2 complex which consequently results in mTOR activation 180. Furthermore, Akt has been shown to directly phosphorylate mTOR at Ser2448residues and consequently activate mTOR 181,182.Therefore, Akt positively regulates mTOR activation by direct phosphorylation at Ser2448as well as by indirect means which involves relieving the repressive effects of the upstream inhibitor TSC1/2 complex. Thus leptin, by virtue of its inherent ability to activate Akt, is expected to increase mTOR phosphorylation and activity. AMPK-SIRT1 pathway The 5AMP activated protein kinase (AMPK) is the master regulatory kinase termed the fuel gauge that integrates signals from upstream me diators and effectors of hormones and cytokines to maintain metabolic homeostasis 183.AMPK activation leads to increase ? -oxidation of fatty acids in the mitochondria and inhibition of lipogenesis 184,185. Multiple lines of evidence have cogently demonstrated that leptin activates AMPK and consequently increases fatty acid oxidation 186-188. One exception to this is the hypothalamic neurons, where leptin inhibits AMPK activation to evoke satiety and other hypothalamic effects of leptin 189-191. In general, AMPK plays a catabolic role and engenders energy production via effects on glucose and lipoide metabolism.AMPK activation also effectuates the induction of the NAD+ dependent deacetylase SIRT1 (silent mating type information regulation 2 homolog) 192,193, a metabolic master regulator unequivocally implicated in ageing and the regulation of living 194-198 as well as regulating metabolism 199,200. The anorexic effect of leptin mediated by the activation of POMC neurons in the hyp othalamus is contingent on SIRT1 expression and activation in the neurons of the arcuate nucleus of the hypothalamus 201. Go to - persona of leptin in Alzheimer diseaseAlzheimer Disease (AD) is a progressive, debilitating and the most prevalent neurodegenerative disorder typified by memory impairment and cognitive dysfunction eventually trail to fatality. The gross pathologic hallmarks of autopsied brains of patients with AD include atrophy with widened sulci and narrow gyri in the profane, parietal, and window dressing lobes as well as the neocortex and cingulated gyrus areas of the cerebral cortex. The entorhinal cortex, amygdala, hippocampus and the para-hippocampal gyrus also exhibit pronounced atrophy due to neuronal loss 202,203.There is a decrease in gross weight of brain by 10-15% in AD patients 202. The thickness of the six cortical layers (cortical ribbon) is commonly reduced by 10-20% in AD 202 and ventricular dilation is apparent prominently in the temporal horn as a consequence of the atrophy of the amygdala and the hippocampus. Furthermore, there is a propensity for the loss of larger neurons than the loss of smaller neurons or glial cells in AD 202. Microscopically, AD is characterized by two most common and distinct hallmark microscopic lesions namely senile plaques and neurofibrillary tangles (NFT).Senile plaques are extraneuronal deposits of accumulated and come amyloid-? (A? ) protein in the brain parenchyma, while the NFT are intraneuronal aggregates of protein tau in the hyperphosphorylated state. Other pathological features of the AD brain include synaptic loss, neuronal and dendritic loss, neuropil threads, granulovacuolar degeneration, dystrophic neurites, Hirano bodies, and cerebrovascular amyloid deposition. There is substantial evidence that leptin modulates A? production and metabolism. Chronic peripheral leptin administration in Tg2576 mice has been reported to reduce the brain A? evels 204. Moreover leptin also decreases the BACE1 activity in SH-SY5Y cell line 204. Leptin decreases tau phosphorylation explicitly at residues Ser202, Ser396, and Ser404in retinoic acidinduced differentiated SH-SY5Y cells, differentiated human NT2 cells (NT2N), and rat primary cortical neurons 205-207. Leptin also increases synaptogenesis and aids in memory formation in the hippocampus and is purported to be a cognitive enhancer 133. Leptin has been shown to convert STP into LTP in hippocampal cultures and hippocampal slices 132.Recent evidence suggests that leptin facilitates spatial learning and memory 130 and also increases neurogenesis in the dentate gyrus of adult mice 134. Recent epidemiological studies have also unequivocally implicated decreased leptin levels in the pathogenesis of AD. In the Framingham prospective study, 785 subjects were followed between 1990 and 1994 from the original Framingham cohort 208. The study concluded that leptin levels were inversely related to the guess of developing dementia of the Alzheimer type 208.A year preceding the findings of Lieb and colleagues, a morphometric study in Japan conducted by Narita and group found higher leptin levels were positively correlated with higher hippocampal wads 209. Leptin decreases Amyloid-? (A? ) levels by attenuating the genesis and augmenting the clearance of the peptide The A? peptide is derived from a two-step successive proteolytic cleavage of Amyloid-? precursor protein (A? PP) 210. In the first step, A? PP is cleaved by the membrane-bound protease BACE1 (? -site APP cleaving enzyme 1) (also called ? secretase) to generate CTF? (carboxy terminal fragment ? ) (also known as C99 fragment) 211-215 which in the second step is subsequently cleaved by the ? -secretase complex to generate A? peptide 216-218. According to the amyloid cascade hypothesis, A? is considered as the culpable factor in the instigation and progression of all the neurodegenerative events that characterize AD 219. A plethora of studies have demonstrated that leptin decreases A? levels in severalin vivoandin vitroparadigms 204,220-223. Leptin has been shown to mitigate A? roduction by extenuating BACE1 activity in neural cultures 204. Recent studies have implicated the AMPK/SIRT1 pathway in the leptin-induced modulation of A? levels 222. Emerging data from our unpublished work has not only corroborated the finding that leptin regulates A? metabolism via SIRT1, but also implicated the ubiquitous transcription factor NF-? B as a SIRT1 target downstream in the modulation of A? genesis (unpublished). Leptin decreases A? levels by targeting all facets of A? metabolism, namely production, clearance, and degradation.We have shown that leptin increases the expression levels of insulin degrading enzyme (IDE) putatively by activating the Akt pathway 223, thus augmenting the degradation of A?. Furthermore, leptin also increases the expression levels of LRP1 223, suggesting that leptin may foster the uptake of A? by astrocytes and microglia o r reuptake of A? by neurons and therefore target A? for intracellular degradation or for clearance across the blood-brain-barrier (BBB). Leptin also effectuates the ApoE-mediated clearance of A? 204.Specifically, leptin dose-dependently increased the LRP1-mediated uptake of ApoE-bound A? , therefore committing A? toward the endosomal/lysosomal degradation pathway 204. Leptin attenuates BACE1 expression and activity The first line of evidence linking leptin signaling dyshomeostasis in the pathogenesis of Alzheimer disease emanated from the work of Tezapsidis and colleagues 204, who demonstrated in neural cultures from transgenic mice that leptin mitigates BACE1 activity by evoking changes in lipoid composition of lipid rafts of cell membranes.Furthermore, the study also demonstrated that the lipolytic ability of leptin as a consequence of increased ? -oxidation of fatty acids and decreasede novosynthesis of fatty acids and triglycerides underlies the mechanical link between the eff ects of leptin on lipid composition of membranes and BACE1 activity. Recent data from our studies 223 and other laboratories 221 cogently demonstrate that leptin negatively regulates BACE1 expression, bothin vitroandin vitroparadigms.Moreover, Greco and colleagues have attributed this effect of reduced BACE1 expression on the ability of leptin to induce PPAR? expression and activation 221. Indeed, leptin is a well characterized inducer of PPAR? expression and activity 220,224. In light of this, it is important to reiterate that multiple lines of evidence exist in current literature demonstrating the role of PPAR? as a negative regulator of BACE1 expression 225. another(prenominal) mediator of leptin induced modulation of BACE1 expression may be the transcription factor STAT3.The BACE1 promoter contains a multitude of STAT3 binding sites 226. Multiple lines of evidence have implicated STAT3 in the regulation of BACE1 expression 226-228. Leptin may also modulate BACE1 activity via the activation of the PI3K/Akt and ERK signaling pathways 229. BACE1 expression is also modulated by the master transcription factor NF-? B 230. We have found that leptin represses NF-? B transcriptional activity via induction of SIRT1 expression and activity and thereby attenuates BACE1 expression (unpublished).Furthermore, inhibition of SIRT1 activity significantly compromised the mitigating effect of leptin on BACE1 expression (unpublished). Therefore, the entire start of discrete signal transduction pathways activated by leptin may be implicated in the modulation of BACE1 expression. Leptin mitigates tau phosphorylation It is now the consensus that tau hyperphosphorylation precedes and leads to PHF formation in NFT 231 and aberrant tau hyperphosphorylation is implicated in neurodegeneration in AD 232-236.Recent studies by Tezapsidis and colleagues as well as our work has cogently demonstrated that leptin decreases hyperphosphorylation of tau, primarily by the activation of known c anonical signal transduction pathway coupled to leptin receptors. Firstly, Grecoet al. demonstratedin vitro, in SH-SY5Y and NTera-2 human neuronal cell lines, that leptin reduces the phosphorylation of tau at Ser202, Ser396, and Ser404residues 205. In the alike study, it was shown that leptin was 300-fold more potent than insulin at mitigating tau phosphorylation and the activation of AMPK pathway was implicated in mediating this effect 205.The following year, the same group systematically investigated the involvement of other signal transduction pathways activated by leptin that may top to the attenuation of tau phosphorylation and concluded that leptin-induced activation of Akt, p38 MAPK, as well as AMPK were all intricately involved 206. Notably, of great mechanistic importance, was the revelation that all the three aforesaid(prenominal) pathways activated by leptin, culminated in the phosphorylation of the tau kinase GSK3? at Ser9residue leading to the inhibition of its kinase activity.Therefore, leptin-induced activation of Akt, p38 MAPK, and AMPK signal transduction pathways converged at the focal point GSK3? , a bona fide tau kinase 206,207. Data from our studies carried out in organotypic slices from the hippocampi of adult rabbits has also cogently demonstrated that leptin inhibits GSK3? -induced tau phosphorylation at AT8 (Ser202, Thr205) and PHF1 (Ser396, Ser404) epitopes via the activation of Akt 223,237. Of greater importance and relevance, was the finding that 8-weeks of leptin treatment in CRND8 transgenic mice resulted in a 2-fold decrease in tau phosphorylation at AT8 and PHF1 epitopes 221.Leptin fosters synaptogenesis and synaptic plasticity Several studies have shown that synaptic dysfunction and synaptic loss are the cardinal hallmarks of incipient AD 238-244. Electron microscopy 238,241,245-248, immunohistochemical and biochemical studies 240,249-251 have demonstrated that synaptic loss in the neocortex and the hippocampus is an early e pisode in Alzheimers disease 252,253. Synaptic loss is also the most important structural correlate of cognitive impairment in AD 250,254-260. Synaptic dysfunction can be detected in patients diagnosed ith mild cognitive impairment (MCI), a condition which may or may not progress to AD and characterized by many as a prodromal state of AD 247,261. Leptin plays an indispensable role in learning, memory, and caution of synaptic plasticity 262. Leptin receptor mutantdb/dbmice andfa/farats have deficits in spatial memory and inadequate short term memory processing as assessed by the Morris water maze 130 and T-maze footshock evasion test paradigms 129. In the CA1 region of the hippocampus, leptin exclusively enhances the NMDA receptor-mediated synaptic transmission 132.Leptin facilitates the trafficking of NMDA receptors to the plasma membrane and this may contribute to the effect of leptin on enhancing the NMDA receptor-mediated current 133. This was also corroborated in aXenopusoocyt e ride system expressing recombinant NMDA receptors 132. Leptin evokes the conversion of STP to LTP in acute hippocampal slices. Further delving into the molecular mechanism underlying this effect has implicated the PI3K/Akt and ERK signaling cascades at the nexus as the inhibitors of these signaling pathways excuse this effect of leptin 132.Furthermore, in the CA1 region of the hippocampus, leptin also fosters the induction of a novel form of LTD and this effect was attributed to NMDA receptor activation 263. The study by Durakoglugil also examined the signal transduction cascades involved in the induction of this novel LTD by leptin and concluded that this effect was contingent on the PI3K signaling cascade, but independent of the ERK signaling pathway 263. In addition to regulating synaptic strength by modulation of LTP and LTD, leptin also fosters synaptogenesis.The leptin deficientob/obmice have decreased synapse density and exogenous leptin corrects this deficit in these mic e 264,265. Leptin also induces the expression of a multitude of pre- and postsynaptic proteins such as synapsin2A and synaptophysin in the hippocampus 266. Leptin also has a profound effect on dendritic morphology. Leptin augments filopodial stabilization, fosters mobility and boosts their density, thus promoting synapse formation 267. Interestingly, this effect of leptin on filopodial stability and density is contingent on ERK signaling pathway and not on the PI3K signaling pathway 267.Leptin increases neuronal choice and mitigates cell death There is growing consensus that leptin is a growth and survival factor in the CNS. Leptin increases the viability of SH-SY5Y cells and suppresses apoptosis by down-regulation of caspase-10 and TRAIL and this effect is contingent on the ability of leptin to activate the JAK-STAT, PI3K-Akt, as well as ERK signaling pathways 268. Leptin has been shown to exert neuro restrictive properties in civil MN9D rat dopaminergic cells against 6-OHDA.Lept in also averted the 6-OHDA-induced dopaminergic cell loss in the substantia nigra of mice when administered intracranially 269. This pro-survival effect of leptin on dopaminergic neurons was attributed to the JAK2-dependent activation of the ERK signaling pathway resulting in increased levels of survival factors p-CREB and BDNF 269. Our recent work has unequivocally demonstrated that leptin upregulates the expression of Insulin-like Growth Factor 1 (IGF-1), a known neurotrophic and survival factor in the brain 270.Leptin has also been shown to attenuate apoptotic cell death of gracious cortical neurons in anin vitrooxygen-glucose deprivation model of global ischemia 271. Furthermore, the study by Zhanget al. , also cogently showed that intraperitoneal administration of leptin in mice reduced the infarct volume and significantly improved behavioral parameters in a middle cerebral artery occlusion (MCAO) model of global ischemia 271. This effect of leptin was attributed to the activ ation of ERK signaling pathway as the general inhibitor of ERK signaling abolished this effect of leptin, bothin vitroandin vivo271.Another study employing hippocampal cultures has demonstrated that leptin inhibits neuronal cell loss in response to growth factor withdrawal and oxidative bruise by evoking JAK-STAT activation leading to enhanced expression Mn-SOD and Bcl-xL and stabilizing the mitochondrial membrane potential 135. Leptin also mitigated neuronal loss in response to excitotoxic insult evoked by glutamate in hippocampal cultures by the aforementioned molecular mechanism 135. Leptin also protected the hippocampal neurons from kainite-induced damage in response to excitotoxicity evoked seizures in a mice model of temporal lobe epilepsy 135.A recent study found that leptin also attenuates MPP+-induced cell death in neuronal cultures via the activation of STAT3 and inducing the expression of UCP-2 that culminates in the obviation of mitochondrial dysfunction by MPP+272. Of particular interest is the finding that cultured cortical neurons secrete prodigious amounts of leptin in response to oxygen-glucose-serum deprivation that results in enhanced expression of IL-1? and increased intransigence to apoptotic cell death 273.Moreover, neutralization of this endogenous leptin with an antibody resulted in increased susceptibility of these cultured cortical neurons to oxygen-glucose-serum deprivation induced cell death 273. The salutary effects of leptin on neuronal viability and function have also been corroborated by electrophysiological studies. One such study has cogently demonstrated that leptin combats the hypoxia-induced inhibition of spontaneously firing hippocampal neurons by activating the BK channels (large conductance Ca2+activated K+channels) 274.Leptin induces proliferation of neuronal progenitors evokes neurogenesis As Alzheimer disease is typified with selective neuronal loss in the hippocampus and other regions of the brain, the debunking o f the dogma that neurogenesis occurs exclusively prenatally and the revelation that neurogenesis persists in the adult mammalian brain has opened novel therapeutic avenues to combat the neuronal loss in AD. Chronic leptin treatment increases hippocampal neurogenesis in mice and induces proliferation of adult hippocampal progenitor cultures 134.This effect of leptin on adult hippocampal neurogenesis is attributed to increased cell proliferation in the dentate gyrus and not enhanced cell differentiation or cell survival 134. The study by Garza and colleagues unequivocally implicated the JAK2-STAT3 and PI3K-Akt signal transduction pathways in the leptin induced enhancement of hippocampal neurogenesis 134. Furthermore, leptin rescues the attenuation in adult hippocampal neurogenesis in a mouse model of chronic unpredictable stress-evoked depression via the inhibition of GSK3? nd subsequent stabilization of ? -catenin 275. Leptin has also been documented to evoke neurogenesis and angioge nesis in a mouse stroke model (Avrahamet al. , 2011). Go to - Conclusion Here we have reviewed the contemporary knowledge on the protective role of the adipokine leptin and its signaling in Alzheimers disease. In conspectus, leptin impinges on all facets of Alzheimers disease pathophysiology (Figure 1). These attributes of leptin such as the decrease in A? production and increase of A? learance, reduction in tau hyperphosphorylation as well as increased synaptogenesis, increased memory, increased spatial learning, and increased neurogenesis catapult leptin treatment as a peculiar therapeutic intervention and an indispensable tool in the elucidation of biochemical mechanisms involved in the etiology of the sporadic form of Alzheimers disease. Marwarha , G. and Ghribi, O. Leptin signaling and Alzheimers disease Marwarha , G. and Ghribi, O. (2012) Leptin signaling and Alzheimers disease. American diary of Neurodegenerative Disease, 1 (3), p. 45-265. Lifestyle nonpharmacological inter ventions can have a deep effect on cognitive aging. We have reviewed the available literature on the effectiveness of corporal activity, understanding stimulation, and socialization on the incidence of dementia and on the course of dementia itself. Even though physical activity appears to be beneficial in both delaying dementia onset and in the course of the disease, more research is needed before intellectual stimulation and socialization can be considered as treatments and prevention of the disease.Through our paper, we found that all three nonpharmacological treatments result benefits to cognition and overall well-being in patients with age-related cognitive impairments. These interventions may be beneficial in the solicitude of dementia. Alzheimers disease (AD) is a neurodegenerative disorder with devastating consequences 1. Despite being the most common cause of dementia, poignant approximately 5. 4 million Americans 2 and almost 50% of people over the age 85 3, no cure ha s yet been discovered.Efforts are also focusing on the development of more effective strategies to slow the progression of AD to increase the quality of life of those affected. Even a two-year delay in disease onset would reduce the prevalence of AD among Americans by two million people within fifty years 4. If an intervention that delayed the onset of AD by five years had been employ back in 1997, we would have seen a 50% reduction in AD incidence 4. inquiry on strategies to slow the development and progression of AD is arguably more important now than ever before, since the number of people with AD is expected to nearly triple over he next forty years 4, and dementia is the most important contributor to disability in the elderly 5. Among others, three nonpharmacological interventions are particularly relevant as they cogency positively influence cognition, general functioning, and overall quality of life. These three strategies arephysical exercise,intellectual stimulation,ands ocial interaction. While there are studies that evaluate the role of individual and multimodal interventions on AD, there is a lack of literature on the combination of all three.The purpose of this paper is to review key areas of the literature that focus on the effects of physical exercise, intellectual stimulation, and socialization strategies on AD evolution, as they collectively play an important role in the management of Alzheimers disease. Physical exercise encapsulates both aerophilous exercises (e. g. , walking and cycling) and nonaerobic exercises (e. g. , strength and resistance training flexibility and balance exercises). For intellectual stimulation, we examine studies that have evaluated the presage effects of either cognitive hobbies (e. g. reading, word puzzles, and card games) or cognitive training (e. g. , computer training games/paradigms that target specific cognitive domains such as memory and attention). Social interaction is defined as the participation of an AD patient in group-related activities, such as mealtime conversations, support groups, or other forms of social engagement. The health benefits attributed to physical activity are numerous and well known. Exercise has been associated with a lower incidence in many chronic diseases, such as coronary heart disease 6, type 2 diabetes 7, obesity 8, cancer 9, bone loss 10, and high blood pressure 11.We have reviewed the effects of physical exercise on cognition. Higher cardiorespiratory fitness has been related to higher scores on tests of cognitive function 12. A meta-analysis of randomized controlled trials examining the relationship between exercise and cognition showed modest improvements in attention, processing speed, executive function, and memory among older adults in the treatment arms 13. This is highly relevant for the elderly population, as it suggests that physical activity can serve as a preventative measure against age-related cognitive decline 14.Several large longitudi nal studies followed older adults without cognitive impairments at baseline and measured rate of incident dementia to clarify the relationship between physical activity and incident cognitive loss. A large prospective study by Podewils et al. identified an inverse relationship between physical activity and dementia guess 15. Compared to no exercise, physical activity has been linked with reduced risks of developing cognitive impairment and dementia 16 with the risk for dementia being further reduced with increasing levels of physical activity.Larson and colleagues found that persons who exercised three or more times per week had a reduced risk of developing dementia compared to those who exercised less, and the reduction was more marked among those with the poorest physical function at baseline 17. These results were corroborated by Buchman et al. who found that participants in the lowest percentiles of physical activity had more than twice the risk of developing dementia than thos e in the highest percentiles of physical activity 18.Furthermore, Lautenschlager et al. demonstrated that these results might be transferable to adults with mild cognitive impairment (MCI), and, thus, at high risk for dementia participants who underwent exercise training showed modest improvements in cognition after six months 19. Physical exercise has, therefore, been recommended as a preventative measure of mild cognitive impairment and dementia 20,21. There is much less research focusing on the effect of physical activity in AD patients.This may be due to the challenges of implementing an exercise regime while managing the behavioral and emotional disturbances in AD patients, particularly in the afterwards stages of the disease. However, the results in the available literature are promising. Early research involving AD patients in nonrandomized controlled trials showed significant cognitive improvements among participants who underwent cycling training and somatic and isotonic-r elaxation exercises 22,23. Physical exercise may have beneficial effects in AD patients beyond cognition as well.A meta-analysis on 30 randomized controlled trials that employed exercise, behavioral and environmental manipulations in patients with cognitive impairment found exercise had positive effects on strength and cardiovascular fitness in addition to improvements in behavior and cognition 2426. Further evidence supporting varied positive effects of exercise on AD can be traced to recent randomized controlled trials of physical exercise regimes on AD patients (Table 1). Compared to controls, patients in the intervention programs showed better physical functioning (functional reach, walking, and mobility).After treatment, these patients also showed improved performance of activities of daily living (ADLs), and less cognitive decline and cognitive improvement in some cases. Physical exercise, therefore, appears to be beneficial for AD patients. While the majority of the studies did not find any differences in depression, one study by Steinberg found increased depression and decreased quality of life in patients who underwent the exercise intervention 31. Further research into the effect of physical exercise on mood and quality of life in AD patients is, therefore, required.When considering the role of exercise on AD, it is important to note that any positive results may be due to a placebo effect, even in randomized controlled trials. However, due to the varied nature of the outcome measures used in these studies, it is unlikely that every intervention group demonstrated significant gains over the controls due to a placebo effect alone. Furthermore, control group members never appeared to show any improvement and a great deal showed higher rates of functional and cognitive decline.Enhanced neuroplasticity might be underlying the improvements seen. Colcombe and colleagues demonstrated that older adults without dementia who performed aerobic exercises had g reater grey and white matter volumes compared to adults who engaged in stretching and toning exercises 38. Exercise has also been associated with functional connectivity between brain networks often affected by age, such as the default mode, frontal parietal, and frontal executive networks, in older adults without dementia 39.While randomized controlled trials in AD patients examining the relationship between neuroplasticity and exercise are underway, correlational studies examining brain volumes and cardiorespiratory fitness have been done. In AD patients, cardiorespiratory fitness has been associated with brain volume. VO2peak, peak oxygen consumption, has been positively correlated with greater whole brain volume and white matter volume 40, notably in the inferior parietal lobule, hippocampal, and parahippocampal regions 41.Future results of randomized controlled trials will improve our knowledge in this field of research. Overall, physical activity offers promising outcomes for cognition and physical health in the elderly population and AD patients. Engagement in intellectually stimulating activities has been linked with reduced risk of developing AD and intellectual stimulation has been widely explored as a nonpharmacological treatment option for dementia 42. Among cognitively ormal older persons, randomized control trials employing intellectual training concluded that cognitive interventions produce protective and potentially long lasting positive effects in various cognitive domains as well as activities of daily living 43. There is also evidence that frequent engagement in hobbies, including reading, puzzles, and games, for at least six hours per week reduces the risk of incident dementia 44. The concept of intellectual stimulation as a preventative measure for dementia in healthy older adults can be parallel to the notion of building a compensatory mechanism or cognitive reserve 4548.Cognitive reserve refers to the hypothesis that individual differenc es shaped by inherent characteristics and external sources including intelligence, years of training, occupation, and intellectual activities, may impart neural protective support against dementia 4547. It has been argued that these collective life experiences may contribute to building cognitive reserve and, thus, provide skills to compensate for AD pathology 4547.In other words, a greater cognitive reserve might delay the appearance of dementia despite the presence of neuropathology, after which a rapid progression of cognitive decline may ensue once pathology is significant enough to result in AD diagnosis. Thus, AD patients with higher information and occupation accomplishments suffer more rapid decline in cognitive abilities when compared to AD patients with less education and occupational attainment following diagnosis 49. Another study by Helzner and colleagues 50 investigated the relationship between premorbid leisure activity and rate of cognitive decline in AD patients. Leisure activities were classified into four categories intellectual, social, physical, and other. Higher-frequency participation in intellectual leisure activities prior to AD diagnosis was associated with delayed AD onset followed by fast-paced cognitive decline. The study by Helzner and colleagues 50 provides evidence for the benefits of intellectual stimulation on slowing down AD development. Besides reducing the risk of dementia, cognitive interventions later in life may affect functional decline in AD.Treiber and colleagues 51 explored the association between engaging in cognitively stimulating activities in late life and the rate of cognitive decline in incident AD. This study included a wide range of intellectual activities that required varying levels of cognitive demand, for example, completing puzzles, reading, watching television, listening to music, and cooking. The results suggested that higher-frequency participation in stimulating activities in early stages of demen tia resulted in slower cognitive decline.However, as time progressed there was an overall decrease in participation in activities, which might reflect the nature of AD in terms of functional abilities. Intellectual stimulation can be divided into several categories including cognitive stimulation, cognitive t