• Users Online: 473
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2015  |  Volume : 10  |  Issue : 9  |  Page : 1349-1355

Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology

1 Center of Clinical and Experimental Research, University of Medicine and Pharmacy Craiova, Romania
2 Department of Psychiatry, University of Medicine Rostock, Germany; Center of Clinical and Experimental Research, University of Medicine and Pharmacy Craiova, Romania
3 Department of Psychiatry, University of Medicine Rostock, Germany; Biochemistry Department, University of Medicine and Pharmacy "Victor Babes" Timisoara, Romania
4 Griffith University School of Medicine, Regenerative Medicine Centre, Brisbane, Australia

Date of Acceptance09-Jul-2015
Date of Web Publication7-Oct-2015

Correspondence Address:
Aurel Popa-Wagner
Department of Psychiatry, University of Medicine Rostock, Germany; Center of Clinical and Experimental Research, University of Medicine and Pharmacy Craiova, Romania

Login to access the Email id

Source of Support: Dr. Raluca Elena Sandu was supported by a POSDRU grant no. 159/1.5/S/136893 grant: "Strategic partnership for the increase of the scientific research quality in medical universities through the award of doctoral and postdoctoral fellowships-DocMed.Net_2.0"., Conflict of Interest: None

DOI: 10.4103/1673-5374.165208

Rights and Permissions

Virtually all drug interventions that have been successful pre-clinically in experimental stroke have failed to prove their efficacy in a clinical setting. This could be partly explained by the complexity and heterogeneity of human diseases as well as the associated co-morbidities which may render neuroprotective drugs less efficacious in clinical practice. One aspect of crucial importance in the physiopathology of stroke which is not completely understood is neuroinflammation. At the present time, it is becoming evident that subtle, but continuous neuroinflammation can provide the ground for disorders such as cerebral small vessel disease. Moreover, advanced aging and a number of highly prevalent risk factors such as obesity, hypertension, diabetes and atherosclerosis could act as "silent contributors" promoting a chronic proinflammatory state. This could aggravate the outcome of various pathological entities and can contribute to a number of subsequent post-stroke complications such as dementia, depression and neurodegeneration creating a pathological vicious cycle. Moreover, recent data suggests that the inflammatory process might be closely linked with multiple neurodegenerative pathways related to depression. In addition, pro-inflammatory cytokines could play a central role in the pathophysiology of both depression and dementia.

Keywords: aging; stroke; neuroinflammation; comorbidities; depression; dementia

How to cite this article:
Sandu RE, Buga AM, Uzoni A, Petcu EB, Popa-Wagner A. Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology. Neural Regen Res 2015;10:1349-55

How to cite this URL:
Sandu RE, Buga AM, Uzoni A, Petcu EB, Popa-Wagner A. Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology. Neural Regen Res [serial online] 2015 [cited 2020 Jul 14];10:1349-55. Available from: http://www.nrronline.org/text.asp?2015/10/9/1349/165208

Conflicts of interest: We have no conflict of interest to declare.

  Introduction Top

Cerebrovascular diseases are one of the most prevalent health care problems in Europe. Total European cost of brain disorders in 2010 was 798 billion € of which 64.1 billion € was related to stroke alone. In many cases, the result of cerebrovascular disorders is a loss of independent living and secondary health problems affecting not only patients but also their families. The number of elderly people is increasing with a number of co-morbidities increasing the risk of cerebrovascular diseases. Thus, strategies in guiding patient selection and patient selection and novel preventive and neuroprotective therapies are urgently needed. Emerging evidence suggests that several diseases show overlapping mechanisms with neuroinflammation as one possible common pathway the leading to an increased risk of cerebrovascular neurological diseases.

Although neuropathological conditions differ in their aetielogy and in the way in which the inflammatory response is mounted, cellular and molecular mechanisms of neuroinflammation are probably similar in aging, hypertension, depression and cognitive impairment or after cerebral insults such as stroke (Allison and Ditor, 2014). Moreover, aging and a number of highly prevalent risk factors such as hypertension, diabetes and atherosclerosis are considered to act as "silent contributors" to neuroinflammation - not only establishing the condition as a central pathophysiological mechanism, but also constantly fuelling it ([Figure 1]). In this review, we describe the relationship between aging, comorbidities and neuroinflammation as the final link which aggravates the outcome of cerebrovascular diseases and precipitates the development of post-event subsequent complications including depression and neurodegenerative disorders.
Figure 1 Neuroinflammation and comorbidities in central nervous system (CNS) pathologies.
Aging, comorbidities and neuroinflammation aggravates the outcome of cerebrovascular diseases and precipitates the development of post-event subsequent complications including depression and neurodegen­erative disorders. SVD: Small vessel disease.

Click here to view

  Cerebral Small Vessel Disease ('Vascular Dementia') and Neuroinflammation Top

In older individuals, inflammatory mechanisms have been linked to the pathogenesis of both dementia and functional impairment. Increasing evidence suggests that systemic and local neuroinflammation significantly contributes to cerebral small vessel disease (cSVD)-vascular dementia. For example, adhesion molecule serum levels are increased in patients with white matter lesions (de Leeuw et al., 2002). A relationship between inflammatory processes and cSVD may also be assumed since chronic inflammation plays an important role in hypertension which is the primary risk factor for cSVD (Schiffrin, 2014). One hypothesis is that these microvascular changes result in a state of chronic hypoperfusion leading to continuous oligodendrocyte death and consecutive degeneration of myelinated fibers. This may not only cause progressive white matter damage on a macroscopic scale, but also may foster the onset of inflammatory processes. Further, increased low-grade inflammation amplifies the risk of stroke (Shimizu et al., 2011). However, in a cross-sectional study investigating the possible association between biomarkers of systemic inflammation and functional status in older patients with late onset Alzheimer's disease and elderly patients with vascular dementia it was found that interleukin 6 (IL-6) plasma levels negatively correlated with vascular dementia (Zuliani et al., 2007).

  Atherosclerosis and Chronic Inflammation Top

Atherosclerosis, a major risk factor for stroke and central nervous system (CNS) tissue destruction, is a disease of arteries characterized by vascular inflammation caused primarily by infiltrated monocytes into the injured vascular wall.

Several studies have suggested that inflammation may be important for accelerated progression of atherosclerosis. In a study investigating the association between inflammatory biomarkers and progression of intracranial large artery stenosis after ischemic stroke, it was found that in addition to traditional risk factors, circulating levels of IL-6 after stroke were associated with future intracranial large artery stenosis progression (Tousoulis et al., 2011). Likewise, it is widely accepted that in addition to other established cardiovascular risk factors, markers of inflammation such as C-reactive protein (CRP) is a strong predictor of subclinical and clinical atherosclerosis (Rizzo et al., 2009) and progression of hemorrhagic stroke (Di Napoli et al., 2012, 2014). Thus, in patients with hypertension, elevated CRP levels may predict clinical events. These patients also showed a significant relationship between clinical events and quintiles of CRP levels (Rizzo et al., 2009). Other studies have reported on pathological vicious cycles related to C-reactive protein and atherosclerosis. For example, elevated circulating levels of C-reactive protein independently predict the development of new plaques in older persons with carotid arteries free from atherosclerotic lesions (Molino-Lova et al., 2011; Shimizu et al., 2013).

Virtually all drug interventions that have been successful pre-clinically in experimental stroke have failed to demonstrate positive results in stroke patients. Our research as well as other group's studies indicate that ignoring the molecular characteristics of ageing and the associated co-factors present in clinical stroke results in disappointing results in clinical trials (Petcu et al., 2010; Murray et al., 2012; Buga et al., 2013; Popa-Wagner et al., 2014).

Studies conducted on aged rats have demonstrated that neurological impairment is more severe and functional recovery less successful than in young rats (Lindner et al., 2003; Buchhold et al., 2007; Popa-Wagner et al., 2011). Indeed, elderly individuals recover less well from stroke than young individuals (Manwani et al., 2011).

  Stroke, Obesity and Neuroinflammation Top

Age represents the most important risk factor for stroke. Virtually all drug interventions that have been successful pre-clinically in experimental stroke have failed to demonstrate positive results in stroke patients.

Our research as well as other group's studies indicate that ignoring the molecular characteristics of ageing and the associated co-factors present in clinical stroke results in disappointing results in clinical trials (Petcu et al., 2010; Buga et al., 2013; Murray et al., 2013; Popa-Wagner et al., 2014).

Epidemiological studies have revealed an age-dependent increase of stroke susceptibility in men and women, with half of all strokes occurring in people over 75 years, and one third of cases in people over 85 years (Roger et al., 2012; Willey et al., 2012). Studies conducted on aged rats have demonstrated that neurological impairment is more severe and functional recovery less successful than in young rats (Lindner et al., 2003; Buchhold et al., 2007; Popa-Wagner et al., 2011). In addition, elderly individuals recover less well from stroke than young individuals (Manwani et al., 2011).

Stroke patients are at highest risk of death in the first weeks after the event, and between 20% to 50% die within the first month depending on type, severity, age, co- morbidity and effectiveness of treatment of complications. Patients who survive may be left with no disability or with mild, moderate or severe disability. Considerable spontaneous recovery occurs up to about six months (Bonita et al., 1988). However, patients with a history of stroke are at risk of a subsequent event of around 10% in the first year and 5% per year thereafter (Burn et al., 2014).

In obese mice, the adipose tissue is characterised by a lower interstitial oxygen partial pressure (PO 2 ) (Ye et al., 2007; Rausch et al., 2008). During surgery, the obese patients present with a lower PO 2 in the subcutaneous adipose tissue of the lateral upper arm compared with non-obese patients (Kabon et al., 2004). Furthermore, abdominal subcutaneous adipose tissue PO 2 is slightly lower in overweight/obese compared with lean subjects (Pasarica et al., 2009). Thus adipose tissue dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes melitus and cardiovascular disease (Goossens et al., 2011).

The obesity paradox has been reported in many articles as an inverse relationship between the body mass index (BMI) and mortality in stroke patients. However, the relationship between BMI and functional recovery in post stroke patients has not been well described (Olsen et al., 2008; Towfighi et al., 2009; Ovbiagele et al., 2011; Ryu et al., 2011; Vemmos et al., 2011; Andersen et al., 2013).

A cohort study from the China National Stroke Registry analyzed the relationship between the body mass index (BMI), mortality and post stroke functional recovery at 3 months after disease onset. This study enrolled and analyzed 10,905 eligible patients with acute ischemic stroke. Favourable functional recovery was seen in 52.4 % of underweight (BMI 18.5 kg/m 2 ), 55.0% of normal weight (BMI 18.5-22.9 kg/m 2 ), 61% of overweight (BMI 23-27.4 kg/m 2 ), 59.2% of obese (27.5-32.4 kg/m 2 ) and 60.3% of severe obese (BMI > 32.5 kg/m 2 ) stroke survivors. The overweight acute ischemic stroke survivors had a better 3-month functional recovery. Remarkably, patients with obesity (BMI less than 32.5 kg/m 2 ) showed a positive outcome. However, severe obesity was associated with higher mortality while an overweight status was not a protective factor of survival at 3 months after stroke (Zhao et al., 2014).

A study evaluating the effect of BMI on stroke rehabilitation conducted in 819 patients revealed that overweighted patients had better functional progression than patients included in other weight categories (Burke et al, 2014). In a large retrospective cohort study from the Danish Stroke Register, 53,812 patients were evaluated for BMI, age, sex, civil status, stroke severity, stroke subtype, a predefined cardiovascular profile, and the socioeconomic status. There was no evidence of an obesity paradox in patients with reported stroke. However, stroke occurred at a significantly younger age in patients with higher BMI (Burke et al., 2014).

In conclusion, obesity could determine a worse outcome in stroke patients, yet it is not known the exact molecular pathways (Howcroft et al., 2013). However, since obesity represents a state of chronic inflammation it is likely that this factor plays a crucial role in the general evolution of these patients.

  Diabetes Mellitus and Metabolic Inflammation Top

Diabetes mellitus (DM) is a great challenge for the healthcare system accounting for ~6% of global mortality in industrialized countries. Half of DM-associated deaths are attributed to cardiovascular (macro- and micro-vascular) complications.

Neuropathic complications are also frequent, occurring in about 60% of people with DM, and often overlap with, and worsen the consequences of vascular disease. Sensory neuropathy is a typical form of peripheral neuropathy characterized by an altered perception of noxious stimuli or ischemic pain. This promotes the foot ulcers caused by pressure or traumas and abrogates warning symptoms during a heart attack.

It is becoming well established that lifestyles, especially dietary habits, greatly affect metabolic health. Bad nutritional habits can lead to metabolic disorders, triggered by a system-wide chronic inflammation, also called metaflammation, metabolic inflammation (Olefsky and Glass, 2010). A metaflammation state can lead to a series of disorders and diseases, including hypertension, metabolic syndrome, CVD, stroke, insulin resistance and type 2 diabetes mellitus (T2DM). It is postulated that lipid hormones including sphingolipids and eicosanoids in concert with cytokines and adipokines play an important role in this process by inducing adverse regulatory responses in target cells such as macrophages. The role of genetics in driving metabolic disease development is strongly indicated by the higher concordance rate of T2DM in monozygotic than in dizygotic twins. It has been estimated that 30% to 70% of T2DM risk can be attributed to genetics (Poulsen et al., 1999). The investigation of gene-environment interactions through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors (Cornelis and Hu, 2012).

Since the completion of the HapMap project and the availability of whole genome SNP assays, genome-wide analysis of correlations between genetic variants (SNPs) and phenotypes has become an important approach to find disease-causative genes. Genome wide SNP typing is often performed in very large groups of human individuals (cohorts), and a large number of loci underlying disease have now been catalogued (http://www.genome.gov/gwastudies/, including variants that increase susceptibility to T2DM. However, these loci confer effects of only modest size and do not add to the clinical prediction of diabetes beyond that of traditional risk factors, such as obesity, physical inactivity, family history of diabetes, and certain clinical parameter. Furthermore, recent studies led to the identification of new genetic loci linking adipocyte and insulin biology to body fat distribution (Locke et al., 2015; Shungin et al., 2015). The combination of GWAS with metabolomics is now breaking new grounds (Bictash et al., 2010), as it allows making associations between SNPs and so-called intermediate phenotypes that can be obtained through exact measurements.

Metabolomics facilitates the exact quantitative measurement of large sets of lipid molecules and other metabolites, and GWAS has allowed the mapping of numerous metabolic phenotypes on the genome, as demonstrated by the discovery of substantial numbers of loci with relative strong effects (Illig et al., 2010; Teslovich et al., 2010; Suhre et al., 2011; Kettunen et al., 2012). Therefore, we could speculate diabetes mellitus is characterised by a state of increased general inflammation including at the CNS level which might impair recovery and outcome in a wide range of neurological conditions.

  Depression and Neuroinflammation Top

Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. In addition to mortality associated with suicide (Kessler et al., 2005), depressed patients are more likely to develop dementia, coronary artery disease and type 2 diabetes (Knol et al., 2006). Depression also complicates the prognosis of other chronic diseases (Evans et al., 2005; Gildengers et al., 2008). However, biological mechanisms underlying depression remains poorly understood.

Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication (Rush et al., 2006). One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression and dementia by a number of putative mechanisms involving neuroinflammation, oxidative stress, endothelial nitric oxide synthase uncoupling, and hyperglutamatergia, as well as their relationships to indirect evidence of neurovascular dysfunction in MDD (Najjar et al., 2013; Zunszain et al., 2013).

Recent evidence has shown that MDD is associated with increased levels of inflammatory markers in the periphery. A number of inflammatory biomarkers (including inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules) in the periphery have been found to be reliably elevated in one third of all depressed patients with a decreased likelihood of response to conventional antidepressants (Lanquillon et al., 2000; Miller et al., 2009; Papakostas et al., 2011). Conversely, patients treated with cytokines for various illnesses are at increased risk of developing major depressive illness (Krishnadas and Cavanagh, 2012). A recent study reported that treatment-resistant depression (TRD) who has highly increased inflammation (i.e., elevated baseline hs-CRP concentration) responded preferentially to infliximab while infliximab-treated participants with a low level of inflammation appeared to do worse than placebo-treated participants (Raison et al., 2013). Of note, increased inflammatory markers in depressed patients have also been associated with remitted stages of depression in response to treatment with conventional antidepressant medications (Sluzewska et al., 1997; Lanquillon et al., 2000; Nemeroff et al., 2003; Baune et al., 2012).

On a background of systemic inflammation, proinflammatory cytokines can access the central nervous system and interfere with serotonin metabolism, and reduce both synaptic plasticity and hippocampal neurogenesis (Maes, 2009; Caraci et al., 2010). Behavioral consequences of these effects of the immune system on the brain include depression (Capuron and Miller, 2011; Raison et al., 2012).

Cross-sectional (Penninx et al., 2003; Tiemeier et al., 2003; Bremmer et al., 2008) and prospective (van den Biggelaar et al., 2007; Milaneschi et al., 2009) epidemiological studies have focused on peripheral inflammatory markers, such as cytokines and acute phase reactans, on the assumption that peripheral inflammatory markers are etiological factors in the development of depressive symptoms (Dantzer et al., 2008a, b; Baune et al., 2012) as well as induce neurotransmitter changes in the brain as seen in depression (Anisman et al., 2008). The most consistent finding has been the association of elevated cytokines IL-6 and IL-8 with depressive symptoms (Baune et al., 2012).

Successful antidepressant treatment may reduce proinflammatory markers by improving perfusion or restore endothelial function (Ghiadoni et al., 2000; Miller et al., 2009; Nagata et al., 2010). Etanercept, a soluble tumor necrosis factor-α receptor, and celecoxib, a cyclo-oxygenase-2 inhibitor, may reduce depressive symptoms in patients with inflammatory diseases (Tyring et al., 2006; Kekow et al., 2010) and infliximab may improve depression in patients with greater pre-treatment inflammation (Raison et al., 2012).

  Depression, Aging and Neuroinflammation Top

Normal aging is characterized by a chronic low-grade, pro-inflammatory state (Bruunsgaard et al., 2001), with an over-expression of systemic inflammatory factors, including pro-inflammatory cytokines (Fagiolo et al., 1992, 1993). Age-associated inflammation in the brain manifests primarily the chronic activation of perivascular and parenchymal macrophages/microglia expressing proinflammatory cytokines and an increased number of astrocytes (Ye and Johnson, 1999).

Given the potential role of inflammation in psychopathology, it is possible that chronically activated inflammatory signals in aging may contribute to increased vulnerability to neuropsychiatric disorders (Capuron et al., 2008). Inflammation in obese women is associated with increased concentrations of inflammatory markers (IL-6, CRP and adipokines) that correlated with increased symptoms of depression and anxiety (Capuron et al., 2010). Conversely, removal of fat tissue surgically was associated with reduced inflammation (Cancello et al., 2005).

The prevalence of depression and cognitive dysfunction is particularly elevated in the elderly and obese subjects. Patients with major depression have an increased onset risk of aging-related diseases affecting the cardiovascular, cerebrovascular, neuroendocrine, metabolic, and immune systems (McIntyre et al., 2007; Bauer, 2008; Wolkowitz et al., 2010). Depression can thus significantly compromise successful aging defined subjectively as freedom from chronic disease and disability, along with high physical and cognitive functioning and social engagement (Jeste et al., 2013).

  Post-stroke Depression and Neuroinflammation Top

Emerging evidence suggests that stroke and traumatic brain injury confer vulnerability to a late-onset of neuropsychaitric and neurocognitive symptoms (Alexopoulos, 2006; Fenn et al., 2013).

Brain injury initiates an exaggerated neuroinflammation by activation of an immune-reactive microglial population as a possible triggering mechanism for the development of depressive-like behavior after injury that may last for weeks and months after the event (Fenn et al., 2013). Importantly, a recent meta-analysis found that the frequency of depressive symptoms even tends to increase in the long-term phase of recovery (Hackett et al., 2005). Depression persists after 20 months in 34% of elderly patients with acute stroke and has been linked to both worse cognitive and physical outcome.

Despite the fact that a high proportion of stroke patients develop mood disorders, the mechanisms underlying PSD have so far received little attention from the field of neurobiology. One major factor involving the development of post-stroke depression could be represented by an age-related microglia activation in response to stroke. Persistent neuronal death causes a prolonged neuroinflammatory response in the infarcted area and may contribute substantially to post-stroke depression. After stroke and traumatic brain injury microglia move toward the site of damage and engulf and clear damaged cellular debris (Nimmerjahn et al., 2005; Hanisch and Kettenmann, 2007; Wakselman et al., 2008). Previously we have shown that aged rats showed a fulminant microglia reaction during the acute phase of stroke that persists for weeks thereafter (Badan et al., 2003; Buga et al., 2012; Fenn et al., 2013). Since microglia has been involved in scavenging synapses, these findings suggest that neuroinflammation represents a significant etiopathogenic molecular pathway.

  Conclusions Top

Although neuropathological conditions differ in aetiology and in the way in which the inflammatory response is mounted, cellular and molecular mechanisms of neuroinflammation are probably similar in aging, depression and cognitive impairment or after cerebral insult such as stroke (Goossens, 2008; Allison and Ditor, 2014). Moreover, a number of highly prevalent risk factors such as obesity hypertension, diabetes and atherosclerosis are increasingly understood to act as "silent contributors" to neuroinflammation - not only establishing the condition as a central pathophysiological mechanism, but also constantly fuelling it. Subtle, but continuous neuroinflammation can provide the ground for disorders such as cSVD and subsequent dementia. Acute neuroinflammation, often in the context of traumatic or ischemic CNS lesions, aggravates the damage and can lead to a number of pathologies such as depression, post-stroke dementia and potentially neurodegeneration. All of those sequelae impair recovery and most of them provide the ground for further cerebrovascular events and a vicious cycle develops.

Therefore, understanding the mechanisms associated with vascular dementia, stroke and related complications is of paramount importance in improving current preventive and therapeutic interventions. However, all these pathological entities are associated with neuroinflammation. A thorough understanding of molecular factors and pathways associated with neuroinflammation will eventually enable the discovery and implementation of new diagnostic and therapeutic strategies for a wide range of neurologial conditions.[98]

  References Top

Alexopoulos GS (2006) The vascular depression hypothesis: 10 years later. Biol Psychiatry 60:1304-1305.  Back to cited text no. 1
Allison DJ, Ditor DS (2014) The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. J Neuroinflammation 11:151.  Back to cited text no. 2
Andersen KK, Olsen TS (2013) Body mass index and stroke: overweight and obesity less often associated with stroke recurrence. J Stroke Cerebrovasc Dis 2:26.   Back to cited text no. 3
Anisman H, Merali Z, Hayley S (2008) Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 85:1-74.  Back to cited text no. 4
Badan I, Buchhold B, Hamm A, Gratz M, Walker LC, Plattparallel D, Kessler Ch, Popa-Wagner A (2003) Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab 23:845-854.  Back to cited text no. 5
Bauer LO (2008) Psychiatric and neurophysiological predictors of obesity in HIV/AIDS. Psychophysiology 45:1055-1063.  Back to cited text no. 6
Baune BT, Smith E, Reppermund S, Air T, Samaras K, Lux O, Brodaty H, Sachdev P, Trollor JN (2012) Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney Memory and Aging Study. Psychoneuroendocrinology 37:1521-1530.  Back to cited text no. 7
Bictash M, Ebbels TM, Chan Q, Loo RL, Yap IK, Brown IJ, de Iorio M, Daviglus ML, Holmes E, Stamler J, Nicholson JK, Elliott P (2010) Opening up the "Black Box": metabolic phenotyping and metabolome-wide association studies in epidemiology. J Clin Epidemiol 63:970-979.  Back to cited text no. 8
Bonita R, Beaglehole R (1988) Recovery of motor function after stroke. Stroke 19:1497-1500.  Back to cited text no. 9
Bremmer MA, Beekman A, Deeg DJ, Penninx BW, Dik MG, Hack CE, Hoogendijk WJ (2008) Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 106:249-255.  Back to cited text no. 10
Bruunsgaard H, Pedersen M, Pedersen BK (2001) Aging and proinflammatory cytokines. Curr Opin Hematol 8:131-136.  Back to cited text no. 11
Buchhold B, Mogoanta L, Suofu Y, Hamm A, Walker L, Kessler Ch, Popa-Wagner A (2007) Environmental enrichment improves functional and neuropathological indices following stroke in young and aged rats. Restor Neurol Neurosci 25:467-484.  Back to cited text no. 12
Buga AM, Di Napoli M, Popa-Wagner A (2013) Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. Biogerontology 14:651-662.  Back to cited text no. 13
Buga AM, Scholz CJ, Kumar S, Herndon J, Alexandru D, Cojocaru GR, Dandekar T, Popa-Wagner A (2012) Identification of new therapeutic targets by genome-wide analysis of gene expression in the ipsilateral cortex of aged rats after stroke. PLoS One 7:e50985.  Back to cited text no. 14
Burke DT, Al-Adawi S (2014) Effect of body mass index on stroke rehabilitation. J Stroke Cerebrovasc Dis 95:1055-1059.  Back to cited text no. 15
Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C (1994) Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 25:333-337.  Back to cited text no. 16
Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K (2005) Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54:2277-2286.  Back to cited text no. 17
Capuron L, Miller AH (2011) Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 130:226-238.  Back to cited text no. 18
Capuron L, Poitou C, Machaux-Tholliez D, Frochot V, Bouillot JL, Basdevant A, Laye S, Clement K (2010) Relationship between adiposity, emotional status and eating behaviour in obese women: role of inflammation. Psychol Med 41:1517-1528.  Back to cited text no. 19
Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, Vogt GJ, MAisano C, Jones L, Murrah NV, Vaccarino V (2008) Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 64:896-900.  Back to cited text no. 20
Caraci F, Copani A, Nicoletti F, Drago F (2010) Depression and Alzheimer's disease: neurobiological links and common pharmacological targets. Eur J Pharmacol 626:64-71.  Back to cited text no. 21
Cornelis MC, Hu FB (2012) Gene-environment interactions in the development of type 2 diabetes: recent progress and continuing challenges. Annu Rev Nutr 32:245-259.  Back to cited text no. 22
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Rev Neurosci 9:46-56.  Back to cited text no. 23
de Leeuw FE, de Groot JC, Oudkerk M, Witteman JC, Hofman A, van Gijn J, Breteler MM (2002) Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 125:765-772.   Back to cited text no. 24
Di Napoli M, Godoy DA , Campi V, Masotti L , Smith CJ, Parry-Jones AR, Hopkins SJ, Slevin M, Papa F, Mogoanta L, Pirici D, Popa-Wagner A (2012) C-reactive protein in intracerebral hemorrhage: time course, tissue localization, and prognosis. Neurology 79:690-699.  Back to cited text no. 25
Di Napoli M, Parry-Jones AR, Smith CJ, Hopkins SJ, Slevin M, Masotti L, Campi V, Singh P, Papa F, Popa-Wagner A, Tudorica V, Godoy DA (2014) C-reactive protein predicts hematoma growth in intracerebral hemorrhage. Stroke 45:59-65.   Back to cited text no. 26
Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, Nemeroff CB, Bremner JD, Carney RM, Coyne JC, Delong MR, Frasure-Smith N, Glassman AH, Gold PW, Grant I, Gwyther L, Ironson G, Johnson RL, Kanner AM, Katon WJ, et al. (2005) Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry 58:175-189.   Back to cited text no. 27
Fagiolo U, Cossarizza A, Santacaterina S, Ortolani C, Monti D, Paganelli R, Franceschi C (1992) Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people. Ann N Y Acad Sci 663:490-493.  Back to cited text no. 28
Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375-2378.  Back to cited text no. 29
Fenn AM, Gensel JC, Huang Y, Popovich PG, Lifshitz J, Godbout JP (2013) Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry 76:575-584.  Back to cited text no. 30
Ghiadoni L, Virdis A, Magagna A, Taddei S, Salvetti A (2000) Effect of the angiotensin II type 1 receptor blocker candesartan on endothelial function in patients with essential hypertension. Hypertension 35:501-506.  Back to cited text no. 31
Gildengers AG, Whyte EM, Drayer RA, Soreca I, Fagiolini A, Kilbourne AM, Houck PR, Reynolds CF, Frank E, Kupfer DJ, Mulsant BH (2008) Medical burden in late-life bipolar and major depressive disorders. Am J Geriatr Psychiatry 16:194-200.   Back to cited text no. 32
Goossens GH (2008) The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 94:206-218.  Back to cited text no. 33
Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP, Konings E, Jocken JW, Cajlakovic M, Ribitsch V, Clément K, Blaak EE (2011) Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 124:67-76.   Back to cited text no. 34
Hackett ML, Anderson CS (2005) Predictors of depression after stroke: a systematic review of observational studies. Stroke 36:2296-2301.  Back to cited text no. 35
Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387-1394.  Back to cited text no. 36
Howcroft TK, Campisi J, Louis GB, Smith MT, Wise B, Wyss-Coray T, Augustine AD, McElhaney JE, Kohanski R, Sierra F (2013) Aging 5:84-93.  Back to cited text no. 37
Illig T, Gieger C, Zhai G, Römisch-Margl WA, Wang-Sattler R, Prehn C, Altmaier E, Kastenmüller G, Kato BS, Mewes HW, Meitinger T, de Angelis MH, Kronenberg F, Soranzo N, Wichmann HE, Spector TD, Adamski J, Suhre K (2010) A genome-wide perspective of genetic variation in human metabolism. Nat Genet 42:137-141.   Back to cited text no. 38
Jeste DV, Palmer BW (2013) A call for a new positive psychiatry of ageing. Br J Psychiatry 202:81-83.  Back to cited text no. 39
Kabon B, Nagele A, Reddy D, Eagon C, Fleshman JW, Sessler DI, Kurz A (2004) Obesity decreases perioperative tissue oxygenation. Anesthesiology 100:274-280.  Back to cited text no. 40
Kekow J, Moots RJ, Emery P, Durez P, Koenig A, Singh A, Pedersen R, Robertson D, Freundlich B, Sato R (2010) Patient-reported outcomes improve with etanercept plus methotrexate in active early rheumatoid arthritis and the improvement is strongly associated with remission: the COMET trial. Ann Rheum Dis 69: 222-225.  Back to cited text no. 41
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE (2005) Life time prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593-602.   Back to cited text no. 42
Kettunen J, Tukiainen T, Sarin AP, Ortega-Alonso A, Tikkanen E, Lyytikäinen LP, Kangas AJ, Soininen P, Würtz P, Silander K, Dick DM, Rose RJ, Savolainen MJ, Viikari J, Kähönen M, Lehtimäki T, Pietiläinen KH, Inouye M, McCarthy MI, Jula A, et al. (2012) Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet 44:269-276.  Back to cited text no. 43
Knol MJ, Twisk JW, Beekman AT, Heine RJ, Snoek FJ, Pouwer F (2006) Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis. Diabetologia 49:837-845.   Back to cited text no. 44
Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83:495-502.  Back to cited text no. 45
Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370-379.  Back to cited text no. 46
Lindner MD, Gribkoff VK, Donlan NA, Jones TA (2003) Long-lasting functional disabilities in middle-aged rats with small cerebral infarcts. J Neurosci 23:10913-10922.  Back to cited text no. 47
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan J, Mägi R, Randall JC, Winkler TW, et al. (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197-206.   Back to cited text no. 48
Maes M (2011) Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 35:664-675.  Back to cited text no. 49
Manwani B, Liu F, Xu Y, Persky R, Li J, McCullough LD (2011) Functional recovery in aging mice after experimental stroke. Brain Behav Immun 25:1689-1700.   Back to cited text no. 50
McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CW, Miranda A, Fulgosi D, Kennedy SH (2007) Should depressive syndromes be reclassified as "metabolic syndrome type II"? Ann Clin Psychiatry 19:257-264.  Back to cited text no. 51
Milaneschi Y, Corsi AM, Penninx BW, Bandinelli S, Guralnik JM, Ferrucci L (2009) Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons: the InCHIANTI study. Biol Psychiatry 65:973-978.  Back to cited text no. 52
Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732-741.  Back to cited text no. 53
Molino-Lova R, Macchi C, Gori AM, Marcucci R, Polcaro P, Cecchi F, Lauretani F, Bandinelli S, Abbate R, Beghi E, Guralnik JM, Ferrucci L (2011) High sensitivity C-reactive protein predicts the development of new carotid artery plaques in older persons. Nutr Metab Cardiovasc Dis 21:776-782.  Back to cited text no. 54
Murray KN, Buggey HF, Denes A, Allan SM (2013) Systemic immune activation shapes stroke outcome. Mol Cell Neurosci 53:14-25.   Back to cited text no. 55
Nagata R, Kawabe K, Ikeda K (2010) Olmesartan an angiotensin II receptor blocker, restores cerebral hypoperfusion in elderly patients with hypertension. J Stroke Cerebrovasc Dis 19:236-240.  Back to cited text no. 56
Najjar S, Pearlman DM, Devinsky O, Najjar A, Zagzag D (2013) Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence. J Neuroinflammation 10:142.  Back to cited text no. 57
Nemeroff CB (2003) The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 37:133-146.  Back to cited text no. 58
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314-1318.  Back to cited text no. 59
Olsen TS, Dehlendorff C, Petersen HG, Andersen KK (2008) Body mass index and poststroke mortality. Neuroepidemiology 30:93-100.  Back to cited text no. 60
Ovbiagele B, Bath PM, Cotton D, Vinisko R, Diener HC (2011) Obesity and recurrent vascular risk after a recent ischemic stroke. Stroke 42:3397-3402.  Back to cited text no. 61
Papakostas GI, Shelton RC, Kinrys G, Henry ME, Bakow BR, Lipkin SH, Pi B, Thurmond L, Bilello JA (2013) Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a Pilot and Replication Study. Mol Psychiatry 18:332-339.  Back to cited text no. 62
Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR (2009) Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58:718-725.   Back to cited text no. 63
Penninx BW, Kritchevsky SB, Yaffe K, Newman AB, Simonsick EM, Rubin S, Rubin S, Ferrucci L, Harris T, Pahor M (2003) Inflammatory markers and depressed mood in older persons: results from the health, aging and body composition study. Biol Psychiatry 54:566-572.  Back to cited text no. 64
Petcu EB, Smith RA, Miroiu RI, Opris MM (2010) Angiogenesis in old-aged subjects after ischemic stroke: a cautionary note for investigators. J Angiogenes Res 2:26.  Back to cited text no. 65
Popa-Wagner A, Buga AM, Kokaia Z (2011) Perturbed cellular response to brain injury during aging. Ageing Res Rev 10:71-79.   Back to cited text no. 66
Popa-Wagner A, Buga AM, Tica AA, Albu CV (2014) Perfusion deficits, inflammation and aging precipitate depressive behaviour. Biogerontology 15:439-448.  Back to cited text no. 67
Poulsen Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219-246.  Back to cited text no. 68
Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H (1999) Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance-a population-based twin study. Diabetologia 42:132-145.  Back to cited text no. 69
Raison CL, Rutherford RD, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2012) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. Arch Gen Psychiatry 3:1-11.  Back to cited text no. 70
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31-41.  Back to cited text no. 71
Rausch ME, Weisberg S, Vardhana P, Tortoriello DV (2008) Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32:451-463.  Back to cited text no. 72
Rizzo M, Corrado E, Coppola G, Muratori I, Mezzani A Novo G, Novo S (2009) The predictive role of C-reactive protein in patients with hypertension and subclinical atherosclerosis. Coron Artery Dis 20:15-20.  Back to cited text no. 73
Rizzo M, Corrado E, Coppola G, Muratori I, Novo G , Novo S (2009) Markers of inflammation are strong predictors of subclinical and clinical atherosclerosis in women with hypertension. Intern Med J 39:539-545.  Back to cited text no. 74
Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, et al. (2012) Executive summary: heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation 125:188-197.  Back to cited text no. 75
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905-1917.  Back to cited text no. 76
Ryu WS, Lee SH, Kim CK, Yoon BW (2011) Body mass index, initial neurological severity and long-term mortality in ischemic stroke. Cerebrovasc Dis 32:170-176.  Back to cited text no. 77
Schiffrin EL (2014) Inflammation, immunity and development of essential hypertension. J Hypertens 32:228-229.   Back to cited text no. 78
Shimizu M, Ishikawa J, Yano Y, Hoshide S, Shimada K, Kario K (2011) The relationship between the morning blood pressure surge and low-grade inflammation on silent cerebral infarct and clinical stroke events. Atherosclerosis 219:316-321.  Back to cited text no. 79
Shimizu K, Shimomura K, Tokuyama Y, Sakurai K, Isahaya K, Takaishi S, Kato B, Usuki N, Shimizu T, Yamada K, Hasegawa Y (2013) Association between inflammatory biomarkers and progression of intracranial large artery stenosis after ischemic stroke. J Stroke Cerebrovasc Dis 22:211-217.   Back to cited text no. 80
Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, Strawbridge RJ, Pers TH, Fischer K, Justice AE, Workalemahu T, Wu JM, Buchkovich ML, Heard-Costa NL, Roman TS, Drong AW, Song C, Gustafsson S, Day FR, Esko T, et al. (2015) New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187-196.  Back to cited text no. 81
Sluzewska A, Sobieska M, Rybakowski JK (1997) Changes in acute-phase proteins during lithium potentiation of antidepressants in refractory depression. Neuropsychobiology 35:123-127.  Back to cited text no. 82
Suhre K, Shin SY, Petersen AK, Mohney RP, Meredith D, Wägele B, Altmaier E; CARDIoGRAM, Deloukas P, Erdmann J, Grundberg E, Hammond CJ, de Angelis MH, Kastenmüller G, Köttgen A, Kronenberg F, Mangino M, Meisinger C, Meitinger T, Mewes HW, et al. (2011) Human metabolic individuality in biomedical and pharmaceutical research. Nature 477:54-60.  Back to cited text no. 83
Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466:707-713.  Back to cited text no. 84
Tiemeier H, Breteler MM, van Popele NM, Hofman A, Witteman JC (2003) Late-life depression is associated with arterial stiffness: a population-based study. J Am Geriatr Soc 51:1105-1110.  Back to cited text no. 85
Tousoulis D, Kampoli AM, Papageorgiou N, Androulakis E, Antoniades C, Toutouzas K, Stefanadis C (2011) Pathophysiology of atherosclerosis: the role of inflammation. Curr Pharm Des 17:4089-4110.  Back to cited text no. 86
Towfighi A, Ovbiagele B (2009) The impact of body mass index on mortality after stroke. Stroke 40:2704-2708.  Back to cited text no. 87
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R (2006) Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebocontrolled randomised phase III trial. Lancet 367:29-35.  Back to cited text no. 88
van den Biggelaar AH, Gussekloo J, de Craen AJ, Frölich M,Stek ML, van der Mast RC, Westendorp RG (2007) Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol 42:693-701.  Back to cited text no. 89
Vemmos K, Ntaios G, Spengos K, Savvari P, Vemmou A, Pappa T, Manios E, Georgiopoulos G, Alevizaki M (2011) Association between obesity and mortality after acute first-ever stroke: the obesity-stroke paradox. Stroke 42:30-36.  Back to cited text no. 90
Wakselman S, Bechade C, Roumier A, Bernard D, Triller A, Bessis A (2008) Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J Neurosci 28:8138-8143.  Back to cited text no. 91
Willey JZ, Ortega-Gutierrez S, Petersen N, Khatri P, Ford AL, Rost NS, Ali LK, Gonzales NR, Merino JG, Meyer BC, Marshall RS (2012) Impact of acute ischemic stroke treatment in patients >80 years of age: the specialized program of translational research in acute stroke (SPOTRIAS) consortium experience. Stroke 43:2369-2375.   Back to cited text no. 92
Wolkowitz OM, Epel ES, Reus VI, Mellon SH (2010) Depress Anxiety Depression gets old fast: do stress and depression accelerate cell aging? Depress Anxiety 27:327-338.  Back to cited text no. 93
Ye J, Gao Z, Yin J, He Q (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118-1128.   Back to cited text no. 94
Ye SM, Johnson RW (1999) Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 93:139-148.  Back to cited text no. 95
Zhao L, Du W, Zhao X, Liu L, Wang C, Wang Y, Xu Y (2014) Favorable functional recovery in overweight ischemic stroke survivors: findings from the China National Stroke Registry. J Stroke Cerebrovasc Dis 23:e201-206.  Back to cited text no. 96
Zuliani G, Guerra G, Ranzini M, Rossi L, Munari MR, Zurlo A, Blè A, Volpato S, Atti AR, Fellin R (2007) High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry 22:305-311.   Back to cited text no. 97
Zunszain PA, Hepgul N, Pariante CM (2013) Inflammation and depression. Curr Topics Behav Neurosci 14:135-151.  Back to cited text no. 98


  [Figure 1]

This article has been cited by
1 Current Research on the Impact of Foreign Language Learning Among Healthy Seniors on Their Cognitive Functions From a Positive Psychology Perspective—A Systematic Review
Blanka Klimova,Marcel Pikhart
Frontiers in Psychology. 2020; 11
[Pubmed] | [DOI]
2 The Main Targets Involved in Neuroprotection for the Treatment of Alzheimer’s Disease and Parkinson Disease
Hayrettin O. Gülcan,Ilkay E. Orhan
Current Pharmaceutical Design. 2020; 26(4): 509
[Pubmed] | [DOI]
3 Electric Stimulation of Neurogenesis Improves Behavioral Recovery After Focal Ischemia in Aged Rats
Adrian Tudor Balseanu,Monica Grigore,Leonard-Radu Pinosanu,Mark Slevin,Dirk M. Hermann,Daniela Glavan,Aurel Popa-Wagner
Frontiers in Neuroscience. 2020; 14
[Pubmed] | [DOI]
4 Long-term treatment with spermidine increases health span of middle-aged Sprague-Dawley male rats
Madalina Filfan,Andrei Olaru,Ion Udristoiu,Claudiu Margaritescu,Eugen Petcu,Dirk M Hermann,Aurel Popa-Wagner
GeroScience. 2020;
[Pubmed] | [DOI]
5 Extrasynaptic CaMKIIa is involved in the antidepressant effects of ketamine by downregulating GluN2B receptors in an LPS-induced depression model
Xiao-Hui Tang,Guang-Fen Zhang,Ning Xu,Gui-Fang Duan,Min Jia,Ru Liu,Zhi-Qiang Zhou,Jian-Jun Yang
Journal of Neuroinflammation. 2020; 17(1)
[Pubmed] | [DOI]
6 Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks
Ariel Angel,Rotem Volkman,Tabitha Grace Royal,Daniel Offen
International Journal of Molecular Sciences. 2020; 21(3): 1144
[Pubmed] | [DOI]
7 Treatment With 2-Pentadecyl-2-Oxazoline Restores Mild Traumatic Brain Injury-Induced Sensorial and Neuropsychiatric Dysfunctions
Serena Boccella,Monica Iannotta,Claudia Cristiano,Fabio Arturo Iannotti,Fabio Del Bello,Francesca Guida,Carmela Belardo,Rosmara Infantino,Flavia Ricciardi,Mario Giannella,Antonio Calignano,Vincenzo Di Marzo,Sabatino Maione,Livio Luongo
Frontiers in Pharmacology. 2020; 11
[Pubmed] | [DOI]
8 Ginsenoside Rg1 promotes cerebral angiogenesis via the PI3K/Akt/mTOR signaling pathway in ischemic mice
Junmin Chen,Xiangjian Zhang,Xiaoxia Liu,Cong Zhang,Wenyan Shang,Jing Xue,Rong Chen,Yuan Xing,Degang Song,Renhao Xu
European Journal of Pharmacology. 2019; : 172418
[Pubmed] | [DOI]
9 Endothelial progenitor cells: Potential novel therapeutics for ischaemic stroke
Ulvi Bayraktutan
Pharmacological Research. 2019; 144: 181
[Pubmed] | [DOI]
10 MicroRNA-22 exerts its neuroprotective and angiogenic functions via regulating PI3K/Akt signaling pathway in cerebral ischemia–reperfusion rats
Xiaodong Wang,Cunxian Shi,Hongxia Pan,Xiaowen Meng,Fuhai Ji
Journal of Neural Transmission. 2019;
[Pubmed] | [DOI]
11 Baseline Body Mass Predicts Average Depressive Symptoms over the Next Two Decades for White but Not Black Older Adults
Shervin Assari
Geriatrics. 2019; 4(1): 14
[Pubmed] | [DOI]
12 Impact of Learning a Foreign Language on the Enhancement of Cognitive Functions Among Healthy Older Population
Martin Valis,Gabriela Slaninova,Pavel Prazak,Petra Poulova,Jaroslav Kacetl,Blanka Klimova
Journal of Psycholinguistic Research. 2019;
[Pubmed] | [DOI]
13 Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds
Oscar Hidalgo-Lanussa,Eliana Baez-Jurado,Valentina Echeverria,Ghulam Md Ashraf,Amirhossein Sahebkar,Luis Miguel Garcia-Segura,Roberto C. Melcangi,George E. Barreto
Journal of Neuroendocrinology. 2019;
[Pubmed] | [DOI]
14 Transplantation of mesenchymal stem cells causes long-term alleviation of schizophrenia-like behaviour coupled with increased neurogenesis
Nikolai Gobshtis,Matanel Tfilin,Vadim E. Fraifeld,Gadi Turgeman
Molecular Psychiatry. 2019;
[Pubmed] | [DOI]
15 Predicting Reactive Astrogliosis Propagation by Bayesian Computational Modeling: the Repeater Stations Model
Jerónimo Auzmendi,Luciano Moffatt,Alberto Javier Ramos
Molecular Neurobiology. 2019;
[Pubmed] | [DOI]
16 Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion
Yue-Hua Wang,Ying-Lin Yang,Xiao Cheng,Jun Zhang,Wan Li,Guan-Hua Du
Neural Regeneration Research. 2019; 14(3): 470
[Pubmed] | [DOI]
17 Astrocyte-derived exosomes suppress autophagy and ameliorate neuronal damage in experimental ischemic stroke
Xiaoxi Pei,Yucheng Li,Liangfu Zhu,Zhilong Zhou
Experimental Cell Research. 2019;
[Pubmed] | [DOI]
18 Insulin Resistance Is a Risk Factor for Overall Cerebral Small Vessel Disease Burden in Old Nondiabetic Healthy Adult Population
Xiaoli Yang,Shufan Zhang,Zhiyuan Dong,Yincui Zi,Yufan Luo,Zhi Jin,Lei Shi,Chen Li,Chuanchen Ren,Danhong Wu
Frontiers in Aging Neuroscience. 2019; 11
[Pubmed] | [DOI]
19 Intravenous Immunoglobulin (IVIg) Induce a Protective Phenotype in Microglia Preventing Neuronal Cell Death in Ischaemic Stroke
Vivien Häußler,Tristan Daehn,Björn Rissiek,Vanessa Roth,Christian Gerloff,Thiruma V. Arumugam,Tim Magnus,Mathias Gelderblom
NeuroMolecular Medicine. 2019;
[Pubmed] | [DOI]
20 Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation
Daniel Henriques,Ricardo Moreira,Jens Schwamborn,Luís Pereira de Almeida,Liliana S. Mendonça
Frontiers in Neuroscience. 2019; 13
[Pubmed] | [DOI]
21 Effects of transcranial random noise stimulation combined with Graded Repetitive Arm Supplementary Program (GRASP) on motor rehabilitation of the upper limb in sub-acute ischemic stroke patients: a randomized pilot study
Valentina Arnao,Marianna Riolo,Francesca Carduccio,Antonino Tuttolomondo,Marco D’Amelio,Filippo Brighina,Massimo Gangitano,Giuseppe Salemi,Paolo Ragonese,Paolo Aridon
Journal of Neural Transmission. 2019;
[Pubmed] | [DOI]
22 Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice
Michael J. Haley,Claire S. White,Daisy Roberts,Kelly O’Toole,Catriona J. Cunningham,Jack Rivers-Auty,Conor O’Boyle,Conor Lane,Oliver Heaney,Stuart M. Allan,Catherine B. Lawrence
Translational Stroke Research. 2019;
[Pubmed] | [DOI]
23 Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function
Emily W. Baker,Holly A. Kinder,Franklin D. West
Brain and Behavior. 2019; : e01214
[Pubmed] | [DOI]
24 Cerebral Small Vessel Disease Burden Is Associated With Poststroke Depressive Symptoms: A 15-Month Prospective Study
Yan Liang,Yang-Kun Chen,Vincent Chung-Tong Mok,De-Feng Wang,Gabor S. Ungvari,Winnie Chiu-Wing Chu,Hee-Ju Kang,Wai-Kwong Tang
Frontiers in Aging Neuroscience. 2018; 10
[Pubmed] | [DOI]
25 Age-related deregulation of TDP-43 after stroke enhances NF-?B-mediated inflammation and neuronal damage
Sai Sampath Thammisetty,Jordi Pedragosa,Yuan Cheng Weng,Frédéric Calon,Anna Planas,Jasna Kriz
Journal of Neuroinflammation. 2018; 15(1)
[Pubmed] | [DOI]
26 Smartphone Applications Can Serve as Effective Cognitive Training Tools in Healthy Aging
Blanka Klimova,Martin Valis
Frontiers in Aging Neuroscience. 2018; 9
[Pubmed] | [DOI]
27 Learning a Foreign Language: A Review on Recent Findings About Its Effect on the Enhancement of Cognitive Functions Among Healthy Older Individuals
Blanka Klimova
Frontiers in Human Neuroscience. 2018; 12
[Pubmed] | [DOI]
28 Endocrine Regulator rFGF21 (Recombinant Human Fibroblast Growth Factor 21) Improves Neurological Outcomes Following Focal Ischemic Stroke of Type 2 Diabetes Mellitus Male Mice
Yinghua Jiang,Ning Liu,Qingzhi Wang,Zhanyang Yu,Li Lin,Jing Yuan,Shuzhen Guo,Bum Ju Ahn,Xiao-Jie Wang,Xiaokun Li,Eng H. Lo,Xiaochuan Sun,Xiaoying Wang
Stroke. 2018; 49(12): 3039
[Pubmed] | [DOI]
29 Exploration of 27 plasma immune markers: a cross-sectional comparison of 64 old psychiatric inpatients having unipolar major depression and 18 non-depressed old persons
Torfinn Lødøen Gaarden,Knut Engedal,Jurate Šaltyte Benth,Marianne Larsen,Bernhard Lorentzen,Tom Eirik Mollnes,Tor Magne Bjølseth,Albert Castellheim
BMC Geriatrics. 2018; 18(1)
[Pubmed] | [DOI]
30 Triggering Receptor Expressed on Myeloid Cells 2, a Novel Regulator of Immunocyte Phenotypes, Confers Neuroprotection by Relieving Neuroinflammation
Qian Zhai,Feng Li,Xiyao Chen,Ji Jia,Sisi Sun,Dandan Zhou,Lei Ma,Tao Jiang,Fuhai Bai,Lize Xiong,Qiang Wang
Anesthesiology. 2017; 127(1): 98
[Pubmed] | [DOI]
31 Post-stroke Fatigue and Depressive Symptoms Are Differentially Related to Mobility and Cognitive Performance
Bradley J. MacIntosh,Jodi D. Edwards,Mani Kang,Hugo Cogo-Moreira,Joyce L. Chen,George Mochizuki,Nathan Herrmann,Walter Swardfager
Frontiers in Aging Neuroscience. 2017; 9
[Pubmed] | [DOI]
32 Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies
Gillipsie Minhas,Deepali Mathur,Balakrishnan Ragavendrasamy,Neel K. Sharma,Viraaj Paanu,Akshay Anand
Frontiers in Neuroscience. 2017; 11
[Pubmed] | [DOI]
33 Chronic cerebral hypoperfusion induces post-stroke dementia following acute ischemic stroke in rats
Dong Bin Back,Kyoung Ja Kwon,Dong-Hee Choi,Chan Young Shin,Jongmin Lee,Seol-Heui Han,Hahn Young Kim
Journal of Neuroinflammation. 2017; 14(1)
[Pubmed] | [DOI]
34 Cellular and Molecular Mechanisms Underlying Non-Pharmaceutical Ischemic Stroke Therapy in Aged Subjects
Raluca Sandu,Danut Dumbrava,Roxana Surugiu,Daniela-Gabriela Glavan,Andrei Gresita,Eugen Petcu
International Journal of Molecular Sciences. 2017; 19(1): 99
[Pubmed] | [DOI]
35 Age-Related Frontal Periventricular White Matter Hyperintensities and miR-92a-3p Are Associated with Early-Onset Post-Stroke Depression
Ji-Rong He,Yu Zhang,Wen-Jing Lu,Huai-Bin Liang,Xuan-Qiang Tu,Fei-Yue Ma,Guo-Yuan Yang,Li-Li Zeng
Frontiers in Aging Neuroscience. 2017; 9
[Pubmed] | [DOI]
36 Ischemic stroke: experimental models and reality
Clemens J. Sommer
Acta Neuropathologica. 2017;
[Pubmed] | [DOI]
37 Potential unfavorable impacts of BDNF Val66Met polymorphisms on metabolic risks in average population in a longevous area
Jun-Hua Peng,Cheng-Wu Liu,Shang-Ling Pan,Hua-Yu Wu,Qing-Hua Liang,Rui-Jing Gan,Ling Huang,Yi Ding,Zhang-Ya Bian,Hao Huang,Ze-Ping Lv,Xiao-Ling Zhou,Rui-Xing Yin
BMC Geriatrics. 2017; 17(1)
[Pubmed] | [DOI]
38 Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension
Sherry A. Beaudreau,Nathan C. Hantke,Nehjla Mashal,Christine E. Gould,Victor W. Henderson,Ruth OæHara
Frontiers in Aging Neuroscience. 2017; 9
[Pubmed] | [DOI]
39 Enlarged Perivascular Spaces in The Centrum Semiovale Are Associated with Poststroke Depression: A 3-month Prospective Study
Yan Liang,Yuen Lai Chan,Min Deng,Yang Kun Chen,Vincent Mok,De Feng Wang,Gabor S. Ungvari,Chiu-wing Winnie Chu,Wai Kwong Tang
Journal of Affective Disorders. 2017;
[Pubmed] | [DOI]
40 A longitudinal study of depression and gestational diabetes in pregnancy and the postpartum period
Stefanie N. Hinkle,Germaine M. Buck Louis,Shristi Rawal,Yeyi Zhu,Paul S. Albert,Cuilin Zhang
Diabetologia. 2016;
[Pubmed] | [DOI]
41 Dementia, Preclinical Studies in Neurodegeneration and its Potential for Translational Medicine in South America
Gloria Patricia Cardona-Gómez,Francisco Lopera
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]
42 Adult obese mice suffer from chronic secondary brain injury after mild TBI
Matthew Sherman,Ming-Mei Liu,Shari Birnbaum,Steven E. Wolf,Joseph P. Minei,Joshua W. Gatson
Journal of Neuroinflammation. 2016; 13(1)
[Pubmed] | [DOI]
43 A Lebanese dietary pattern promotes better diet quality among older adults: findings from a national cross-sectional study
Lamis Jomaa,Nahla Hwalla,Leila Itani,Marie Claire Chamieh,Abla Mehio-Sibai,Farah Naja
BMC Geriatrics. 2016; 16(1)
[Pubmed] | [DOI]
44 A roadmap for investigating the role of the prion protein in depression associated with neurodegenerative disease
Danielle Beckman,Rafael Linden
Prion. 2016; 10(2): 131
[Pubmed] | [DOI]
45 The effects of fisetin on lipopolysaccharide-induced depressive-like behavior in mice
Xuefeng Yu,Xi Jiang,Xiangming Zhang,Ziwei Chen,Lexing Xu,Lei Chen,Guokang Wang,Jianchun Pan
Metabolic Brain Disease. 2016;
[Pubmed] | [DOI]
46 Impaired White Matter Connections of the Limbic System Networks Associated with Impaired Emotional Memory in Alzheimeræs Disease
Xiaoshu Li,Haibao Wang,Yanghua Tian,Shanshan Zhou,Xiaohu Li,Kai Wang,Yongqiang Yu
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]
47 Environmental Enrichment Modified Epigenetic Mechanisms in SAMP8 Mouse Hippocampus by Reducing Oxidative Stress and Inflammaging and Achieving Neuroprotection
Christian Griñan-Ferré,Dolors Puigoriol-Illamola,Verónica Palomera-Ávalos,David Pérez-Cáceres,Júlia Companys-Alemany,Antonio Camins,Daniel Ortuño-Sahagún,M. Teresa Rodrigo,Mercè Pallàs
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]
48 Glial Modulation by N-acylethanolamides in Brain Injury and Neurodegeneration
María I. Herrera,Rodolfo Kölliker-Frers,George Barreto,Eduardo Blanco,Francisco Capani
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]
49 Abnormal Subcortical Brain Morphology in Patients with Knee Osteoarthritis: A Cross-sectional Study
Cui Ping Mao,Zhi Lan Bai,Xiao Na Zhang,Qiu Juan Zhang,Lei Zhang
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]
50 Long-Term Outcomes after Stroke in Elderly Patients with Atrial Fibrillation: A Hospital-Based Follow-Up Study in China
Yuguang Zhao,Chunying Zou,Cui Wang,Yongbo Zhang,Shuang Wang
Frontiers in Aging Neuroscience. 2016; 8
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Atherosclerosis ...
Stroke, Obesity ...
Diabetes Mellitu...
Depression and N...
Depression, Agin...
Post-stroke Depr...
Cerebral Small V...
Article Figures

 Article Access Statistics
    PDF Downloaded597    
    Comments [Add]    
    Cited by others 50    

Recommend this journal