Article

Is Alzheimer's Disease Autoimmune Inflammation of the Brain That Can be Treated With Nasal Nonsteroidal Anti-Inflammatory Drugs?

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  • Severn Health Solutions
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Abstract

The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.

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... Of course, it would be important to account for other age-related disorders that patients might be suffering from such as diabetes or cardiovascular diseases that could further exacerbate the ongoing condition or contribute to the inflammatory state. Related to this concept, as stated above autoimmune disorders are highly prevalent in women compared to men, however the mechanism for this bias is not clearly understood [47]. It can be speculated that the inflammatory state of women may lead to an increase in susceptibility to AD. ...
... It can be speculated that the inflammatory state of women may lead to an increase in susceptibility to AD. Indeed, some studies characterize AD as an autoimmune disease not just for understanding the pathophysiology but also for treatment purposes [47]. ...
... Because microglia can cause neurotoxic or neuroprotective effects by dynamically switching between M1 and M2 phenotypes following stimulation, inhibiting overactivated M1 polarisation seems to be a feasible strategy for neuroprotection. However, there is evidence that inhibition of the M1 phenotype alone is unlikely to provide overall benefits [52,53]. Compared to simply inhibiting M1 polarisation, the timely conversion of M1 to M2 microglia is considered a more promising strategy for treating SCI [54]. ...
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Spinal cord injury (SCI) is a highly disabling disorder for which few effective treatments are available. Grape seed proanthocyanidins (GSPs) are polyphenolic compounds with various biological activities. In our preliminary experiment, GSP promoted functional recovery in rats with SCI, but the mechanism remains unclear. Therefore, we explored the protective effects of GSP on SCI and its possible underlying mechanisms. We found that GSP promoted locomotor recovery, reduced neuronal apoptosis, increased neuronal preservation, and regulated microglial polarisation in vivo. We also performed in vitro studies to verify the effects of GSP on neuronal protection and microglial polarisation and their potential mechanisms. We found that GSP regulated microglial polarisation and inhibited apoptosis in PC12 cells induced by M1-BV2 cells through the Toll-like receptor 4- (TLR4-) mediated nuclear factor kappa B (NF-κB) and phosphatidylinositol 3-kinase/serine threonine kinase (PI3K/AKT) signaling pathways. This suggests that GSP regulates microglial polarisation and prevents neuronal apoptosis, possibly by the TLR4-mediated NF-κB and PI3K/AKT signaling pathways.
... For instance, TOMM40 is a shared disease-associated gene between AD and Type II diabetes (Greenbaum et al., 2014). Recent studies showing autoimmune diseases have closed relation with AD (D' Andrea, 2005;Lehrer and Rheinstein, 2015;Wotton and Goldacre, 2017). Among all the genes we identified through TWAS method, eight of them are related to autoimmune diseases. ...
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Alzheimer’s disease (AD) is the most common cause of dementia. It is the fifth leading cause of death among elderly people. With high genetic heritability (79%), finding the disease’s causal genes is a crucial step in finding a treatment for AD. Following the International Genomics of Alzheimer’s Project (IGAP), many disease-associated genes have been identified; however, we do not have enough knowledge about how those disease-associated genes affect gene expression and disease-related pathways. We integrated GWAS summary data from IGAP and five different expression-level data by using the transcriptome-wide association study method and identified 15 disease-causal genes under strict multiple testing (α < 0.05), and four genes are newly identified. We identified an additional 29 potential disease-causal genes under a false discovery rate (α < 0.05), and 21 of them are newly identified. Many genes we identified are also associated with an autoimmune disorder.
... Moreover, longterm use of anti-inflammatory drugs (NSAIDS) reduces the risk of developing AD [42] (decreased plaque burden pathology/increased cognitive function/linked to reduced microglial activation), supporting therapeutic immunemodulatory approaches against AD progression. An important note is that these benefits of NSAID treatment cannot be obtained in established AD [43]. This implies that inflammation precedes neuronal loss in the disease. ...
Article
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Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD) and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA) levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia.
... Alzheimer's dementia is the most common cause of agingrelated dementia, associated with chronic inflammation and T lymphocyte-mediated degeneration of cholinergic myelinated large axons in the basal forebrain, resulting in severe cognitive impairment and eventually death (24)(25)(26). Rats immunized with adjuvated extracts of cholinergic neurons from the electric fish, Torpedo, develop experimental autoimmune dementia (EAD) resembling human AD (27). It was found that the intermediate neurofilament heavy (NFH) protein is the most likely pSAg in these extracts, capable of inducing EAD in rats (28). ...
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... [49] For instance, TOMM40 is a shared disease-associated gene between AD and Type II diabetes [50]. Recent studies showing autoimmune diseases have closed relation with AD [51][52][53]. Among all the genes we identified through TWAS method, eight of them are related to autoimmune diseases. ...
Preprint
Alzheimer's disease is the most common cause of dementia. It is the fifth-leading cause of death among elderly people. With high genetic heritability (79%), finding disease causal genes is a crucial step in find treatment for AD. Following the International Genomics of Alzheimer's Project (IGAP), many disease-associated genes have been identified; however, we don't have enough knowledge about how those disease-associated genes affect gene expression and disease-related pathways. We integrated GWAS summary data from IGAP and five different expression level data by using TWAS method and identified 15 disease causal genes under strict multiple testing (alpha<0.05), 4 genes are newly identified; identified additional 29 potential disease causal genes under false discovery rate(alpha < 0.05), 21 of them are newly identified. Many genes we identified are also associated with some autoimmune disorder.
... Moreover, some iron chelators were found beneficial in AD and Parkinson's disease (PD), possibly pointing to the role of autoimmune inflammation in these disorders (75)(76)(77). Indeed, over the past decade, several studies have associated autoimmunity with AD as serum and CSF autoantibodies against β-amyloid, tau, ceramide and adenosine triphosphate (ATP) synthase were detected in this disorder (35,(78)(79)(80)(81)(82). Interestingly, these molecules were also associated with iron and NLRP3, making it worthwhile to search for ASC autoantibodies in AD (83)(84)(85)(86)(87). ...
Article
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Alzheimer's disease, the most common form of dementia, is marked by progressive cognitive and functional impairment believed to reflect synaptic and neuronal loss. Recent preclinical data suggests that lipopolysaccharide (LPS)-activated microglia may contribute to the elimination of viable neurons and synapses by promoting a neurotoxic astrocytic phenotype, defined as A1. The innate immune cells, including microglia and astrocytes, can either facilitate or inhibit neuroinflammation in response to peripherally applied inflammatory stimuli, such as LPS. Depending on previous antigen encounters, these cells can assume activated (trained) or silenced (tolerized) phenotypes, augmenting or lowering inflammation. Iron, reactive oxygen species (ROS), and LPS, the cell wall component of gram-negative bacteria, are microglial activators, but only the latter can trigger immune tolerization. In Alzheimer's disease, tolerization may be impaired as elevated LPS levels, reported in this condition, fail to lower neuroinflammation. Iron is closely linked to immunity as it plays a key role in immune cells proliferation and maturation, but it is also indispensable to pathogens and malignancies which compete for its capture. Danger signals, including LPS, induce intracellular iron sequestration in innate immune cells to withhold it from pathogens. However, excess cytosolic iron increases the risk of inflammasomes' activation, microglial training and neuroinflammation. Moreover, it was suggested that free iron can awaken the dormant central nervous system (CNS) LPS-shedding microbes, engendering prolonged neuroinflammation that may override immune tolerization, triggering autoimmunity. In this review, we focus on iron-related innate immune pathology in Alzheimer's disease and discuss potential immunotherapeutic agents for microglial de-escalation along with possible delivery vehicles for these compounds.
... Auto-immune conditions are also under discussion as drivers for AD. It is straight-forward to see that an auto-immune response in the brain could start chronic inflammation responses which eventually lead to AD (Korczyn and Vakhapova, 2007;Lehrer and Rheinstein, 2015). The NIH decided to fund further investigations of this link with AD (McCarthy, 2014). ...
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Type 2 diabetes is a risk factor for developing Alzheimer’s disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common – they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid.
... Overall, there is growing preclinical evidence that transplantation of ADSCs and/or their exosomes, may potentially prevent the neurodegeneration associated with AD [86][87][88]. The autoimmune component of this disease remains to be elucidated [89][90][91]. The use of ADSCs, exosomes, and SVF have all shown promising results in experimental models [20,84,85,87,[92][93][94][95][96][97][98]. ...
Article
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... For instance, the stronger immune responses observed in females result in a lower burden of viral, bacterial, and parasitic infections and better vaccine responsiveness (Klein & Flanagan, 2016); however, they also contribute to greater susceptibility to inflammatory and autoimmune diseases. Systemic lupus erythematosus, multiple sclerosis, autoimmune myocarditis, and rheumatoid arthritis are all more prevalent in females (Schurz et al., 2019), as is AD, which has been characterized by some as an autoimmune disease (Lehrer & Rheinstein, 2015). Since the immune system regulates neuronal development and synaptic refinement (Thion & Garel, 2017), sex differences in immune response during critical stages of CNS development may program mental health throughout the individual's lifespan. ...
Chapter
Women are known to have a significantly higher lifetime risk of developing Alzheimer’s disease (AD) and recent research shows that they also appear to suffer greater cognitive deterioration than men at the same disease stage. However, the exact mechanisms underlying this prevalence remain elusive. The purpose of this review is to examine the potential role of neuroinflammation and microglia in driving this sex difference in AD. We first introduce the dual role of microglia in AD, describing their transition from being neuroprotective, in reducing amyloid burden during earlier stages of disease, to their pathological role in exacerbating tau pathology in the later stages. We then describe sex differences in the immune system and in microglial maturation and activities as well as how immune activation in early life may modulate brain function later in life. Lastly, sex differences in microglial function are described in the contexts of aging and AD among other neurodegenerative conditions.
... It has to be considered as well that AD is discussed as an autoimmune disorder [48,49]. Taking into account that the expression of costimulatory molecules was found to be altered in autoimmune disorders and is discussed as potential target for treatment [50,51], our findings might help to find new treatment opportunities for AD patients. ...
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Although the expression of co-stimulatory molecules plays an important role in the immune system, only little is known about their regulation in dementias. Therefore, we determined the expression of CD28, ICOS (CD278) and CTLA-4 (CD152) by CD4 + and CD8 + T cells in the peripheral blood of patients with mild cognitive impairment (MCI; N = 19), Alzheimer’s disease (AD; N = 51), vascular dementia (VD; N = 21) and frontotemporal dementia (FTD; N = 6) at the point in time of diagnosis compared to 19 non-demented elderly persons. The expression of CD28 and ICOS by CD4 + and CD8 + T cells was not changed in AD, FTD or VD patients. The expression of the negative regulator CTLA-4 was increased by CD4 + T cells from AD and FTD patients and by CD8 + T cells from VD patients. The classification of the AD patients according to the severity of the disorder showed stage-dependent alterations of CD28, ICOS and CTLA-4 expression. In AD patients, the correlation analysis showed an association between the decline in CD28 + T cells and the increase in CTLA-4 + T cells with cognitive decline, measured by the mini-mental state examination (MMSE), tau proteins and Amyloid-β, important AD biomarkers in cerebrospinal fluid (CSF). In FTD patients, a positive association between Q Albumin, a marker for blood-CSF-barrier function, and CD28 and a negative correlation between Q Albumin and ICOS expression were determined. Our data suggest a dysregulated balance between the expression of negative and positive co-stimulatory molecules by T cells in AD patients, which might contribute to chronic inflammation observed in dementia.
... Currently, there is no panacea-no magic bullet therapy available in either cholinesterase inhibitors being used or amyloid antibody administration being contemplated. Indeed, the single medication or single treatment modality has failed to ameliorate the heterogeneous pathologies encountered in AD (Aisen et al. 2008;Aisen and Vellas 2013;Doody et al. 2013;Lehrer and Rheinstein 2014). Pragmatically, therefore, a host of pathologies will require a host of correspondingly appropriate treatment strategies/modalities (Chan et al. 2012;Bredesen 2014). ...
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Female/male ratios of autoimmune diseases range from 10:1 to 1:3, with similar severity between the sexes. Men and women respond similarly to the infection and to vaccination, arguing against intrinsic sex differences in immune response. In autoimmune-like illnesses caused by environmental agents sex discrepancy is explained by differences in exposure. Endogenous hormones could cause sex discrepancy if their effect is a threshold off-on switch rather than quantitatively variable. X-inactivation and imprinting could cause sex discrepancy. Other possibilities include chronobiologic differences and pregnancy and menstruation biologies in which men differ from women.
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Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.
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Alzheimer's disease may result from low-grade inflammation of the brain, and the characteristic amyloid β may be a protective response. Epidemiological observation indicates that long-term oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to patients having rheumatoid arthritis results in reduced risk and delayed onset of Alzheimer's disease. However, oral ibuprofen, flurbiprofen, and other NSAIDs are not an effective treatment. The NSAIDs may work as an Alzheimer's preventive but not a treatment because the oral dose to the brain is too small, 1% to 2% of the total plasma concentration. The NSAID brain dose could be significantly increased by delivering the drug intranasally. Flurbiprofen would be preferable to ibuprofen because flurbiprofen has 12&frac12; times the potency of ibuprofen. The smaller nasal dose of flurbiprofen than ibuprofen could significantly increase patient compliance. Alzheimer's disease starts in the entorhinal cortex, which is closely connected to the olfactory nerves, and spreads anatomically in a defined pattern. Therefore, a nasal NSAID would readily reach the region of the brain where it is most likely to be therapeutic.
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A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer’s disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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It is known that autoimmune diseases cumulatively affect 5–10% of the general population.Although knowledge of pathogenesis has become more refined, laboratory diagnosis more accurate, and therapy more effective, the reasons for the female preponderance of these conditions remain unclear. The most intriguing theory to explain the female preponderance is currently related to sex chromosomes, as women with autoimmune diseases manifest a higher rate of circulating cells with a single X chromosome (i.e. X monosomy). In addition, there have been several reports on the role of X chromosome gene dosage through inactivation or duplication in autoimmunity. Taken together, sex chromosome changes might constitute the common trait of the susceptibility to autoimmune diseases.
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Background: Alzheimer's disease (AD) is the most common form of dementia. The incidence of AD rises exponentially with age and its prevalence will increase significantly worldwide in the next few decades. Inflammatory processes have been suspected in the pathogenesis of the disease. Objectives: To review the efficacy and side effects of aspirin, steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AD, compared to placebo. Search methods: We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 12 April 2011 using the terms: aspirin OR "cyclooxygenase 2 inhibitor" OR aceclofenac OR acemetacin OR betamethasone OR celecoxib OR cortisone OR deflazacort OR dexamethasone OR dexibruprofen OR dexketoprofen OR diclofenac sodium OR diflunisal OR diflusinal OR etodolac OR etoricoxib OR fenbufen OR fenoprofen OR flurbiprofen OR hydrocortisone OR ibuprofen OR indometacin OR indomethacin OR ketoprofen OR lumiracoxib OR mefenamic OR meloxicam OR methylprednisolone OR nabumetone OR naproxen OR nimesulide OR "anti-inflammatory" OR prednisone OR piroxicam OR sulindac OR tenoxicam OR tiaprofenic acid OR triamcinolone OR NSAIDS OR NSAID. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (including MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries (including national, international and pharmacuetical registries) and grey literature sources. Selection criteria: All randomised controlled trials assessing the efficacy of aspirin, steroidal and non-steroidal anti-inflammatory drugs in AD. Data collection and analysis: One author assessed risk of bias of each study and extracted data. A second author verified data selection. Main results: Our search identified 604 potentially relevant studies. Of these, 14 studies (15 interventions) were RCTs and met our inclusion criteria. The numbers of participants were 352, 138 and 1745 for aspirin, steroid and NSAIDs groups, respectively. One selected study comprised two separate interventions. Interventions assessed in these studies were grouped into four categories: aspirin (three interventions), steroids (one intervention), traditional NSAIDs (six interventions), and selective cyclooxygenase-2 (COX-2) inhibitors (five interventions). All studies were evaluated for internal validity using a risk of bias assessment tool. The risk of bias was low for five studies, high for seven studies, and unclear for two studies.There was no significant improvement in cognitive decline for aspirin, steroid, traditional NSAIDs and selective COX-2 inhibitors. Compared to controls, patients receiving aspirin experienced more bleeding while patients receiving steroid experienced more hyperglycaemia, abnormal lab results and face edema. Patients receiving NSAIDs experienced nausea, vomiting, elevated creatinine, elevated LFT and hypertension. A trend towards higher death rates was observed among patients treated with NSAIDS compared with placebo and this was somewhat higher for selective COX-2 inhibitors than for traditional NSAIDs. Authors' conclusions: Based on the studies carried out so far, the efficacy of aspirin, steroid and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.
Article
Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.
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Introduction: Nasal drug delivery that exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain is being widely explored by pharmaceutical companies, for the delivery of challenging drugs. Low-molecular-weight and lipophilic drugs are effectively absorbed by the intranasal route for efficacious brain targeting; however, high-molecular-weight and hydrophilic drugs present challenges in intranasal delivery. Areas covered: The present review critically evaluates the physicochemical properties of drugs and formulation variables that influence brain targeting by the intranasal route. It also encompasses the influence of physiological factors of the nose that can influence absorption and the strategies utilized to increase nasal drug absorption. Expert opinion: The challenges of drug delivery to the brain can be overcome by chemical and pharmaceutical approaches; current research is focused on developing novel drug delivery systems for both local and systemic actions. Nose-to-brain targeting has vast potential for commercialization, as these systems allow the lowering of doses, by direct targeting of the active molecule that provides easy attainment of the effective concentration at the target site. Consequently, these systems are being explored for the delivery of biologically active molecules, to treat the ailments of the CNS and various proteins, amino acids and hormones.
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The toxicity of ibuprofen, 2-(4-isobutylphenyl)propionic acid, a nonsteroidal agent with anti-inflammatory, analgesic, and antipyretic properties, was investigated in mice, rats, and dogs after single-dose oral or parenteral administration, and in rats and dogs after repeated oral administration for periods of up to 6 months. Ibuprofen induced gastrointestinal lesions, being more ulcerogenic in dogs than in rats; this difference in species susceptibility may well be related to the drug being more persistent in dog plasma. Organ weight changes occurring in rats were not associated with histologic abnormalities and were reversed when dosing ceased. Doses toxic to rats and rabbits were devoid of embryotoxic or teratogenic activity though ibuprofen or its metabolites entered the fetal circulation. Ibuprofen administered orally was rapidly absorbed in rats, rabbits, and dogs. Absorption in rats was shown to occur mainly from the intestine and to a lesser, though significant, extent from the stomach. Four metabolites of ibuprofen were detected in rabbit plasma, 3 of these also in rat plasma, but none in dog plasma. Distribution studies with ibuprofen-14C revealed that repeated oral dosing of rats led to some accumulation of radioactivity in the adrenals, ovaries, thyroid, skin, and fat, without structure or function being affected. Dogs, however, had high levels only in bile.
Article
(i) To determine the prevalence of multiple sclerosis (MS) in New South Wales and South Australia; (ii) to compare these prevalences with those in other areas of Australia and to determine the relationship between prevalence and latitude; (iii) to examine the relative contribution of genetic and environmental factors in the aetiology of the disease in Australia; and (iv) to ascertain whether there had been a change in the frequency of the disease since 1961. The crude prevalence of MS in New South Wales on prevalence day (National Census Day, 30 June 1981) was 37.2/100,000 and the age-standardised prevalence 36.6/100,000. The female:male ratio was 2.3:1. The crude prevalence in South Australia was 29.4/100,000 and the age-standardised prevalence 28.8/100,000. The female:male ratio was 2.4:1. No Aborigines or Torres Strait Islanders with MS were identified. There was a significant increase in the prevalence with increasing south latitude in Australia, MS being about seven times more frequent in Hobart than in tropical Queensland, but no genetic differences were found in the surveyed population in different parts of Australia. A significant increase in the prevalence of MS occurred in most areas of Australia between 1961 and 1981, but this may not reflect a true increase in incidence. The increasing prevalence with increasing south latitude cannot readily be explained by genetic susceptibility, and suggests that environmental factors are important for expression of the disease.
Article
Alzheimer's Disease (AD) is a particular form of degenerative dementia probably due to deposit in the brain cortex of a non soluble protein called beta-A4 amyloid in senile plaque form. beta A4 is an aberrant mutant proteolytic product of Amyloid Protein Precursor (APP) codified on chromosome 21. Trisomy 21 is responsible for Down's Syndrome (DS). Down's patients have been shown to develop a form of Alzheimer's after 50 years of age, and high blood levels of antithyroid antibodies are also present in a significant percentage of these cases. In the present investigation, antithyroid antibody titres have been studied by means of RIA in group of 34 AD patients. As compared to 30 non-demented controls, AD subjects showed a significant increase in the mean values of antithyroglobulin (TgAb) and antimicrosomial (MCSAb) autoantibodies. The physiopathological relationship regarding this association is discussed.
Article
In a longitudinal study of 1,686 participants in the Baltimore Longitudinal Study of Aging, we examined whether the risk of Alzheimer's disease (AD) was reduced among reported users of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). In addition, we examined use of acetaminophen, a pain-relief medication with little or no anti-inflammatory activity, to assess the specificity of the association between AD risk and self-reported medications. Information on use of medications was collected during each biennial examination between 1980 and 1995. The relative risk (RR) for AD decreased with increasing duration of NSAID use. Among those with 2 or more years of reported NSAID use, the RR was 0.40 (95% confidence interval [CI]: 0.19-0.84) compared with 0.65 (95% CI: 0.33-1.29) for those with less than 2 years of NSAID use. The overall RR for AD among aspirin users was 0.74 (95% CI: 0.46-1.18), and no trend of decreasing risk of AD was observed with increasing duration of aspirin use. No association was found between AD risk and use of acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was no trend of decreasing risk with increasing duration of use. These findings are consistent with evidence from cross-sectional studies indicating protection against AD risk among NSAID users and with evidence suggesting that one stage of the pathophysiology leading to AD is characterized by an inflammatory process. NEUROLOGY 1997;48: 626-632
Article
We investigated blood-brain barrier (BBB) function in relation to Alzheimer's disease (AD) and vascular dementia (VAD) in the very elderly. Sixty-five 85-year-old persons from a population-based sample were followed for 3 years; 29 were demented at age 85 (13 with AD, 14 with VAD, and 2 with other dementias), 7 developed dementia during follow-up, and 29 remained nondemented. CSF/serum albumin ratio was used as as a measure of BBB function. Dementia was defined according to the DSM-III-R, AD according to the NINCDS-ADRDA criteria, and VAD according to the NINDS-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria. Mean CSF/serum albumin ratio was higher in all dementias (8.5 +/- 4.3; p = 0.007) and in the subtypes AD (8.9 +/- 5.3; p = 0.046) and VAD (8.7 +/- 3.5; p = 0.002) than in nondemented individuals (versus 6.5 +/- 2.0), but it was not related to dementia severity. Nondemented women at age 85 (n = 3) who developed dementia during the follow-up had a higher CSF/serum albumin ratio than those not developing dementia (10.4 +/- 2.0 versus 6.0 +/- 1.9; p = 0.007). Nondemented individuals lacking the apolipoprotein E epsilon3 allele (n = 4) had a higher CSF/serum albumin ratio (9.3 +/- 0.8 versus 6.6 +/- 2.1; p = 0.029) than other individuals. A relative BBB dysfunction is associated with both AD and VAD among very elderly individuals. This finding is possibly found early in the disease before the onset of clinical dementia.
Article
To relate performance on tests of cognitive ability to the subsequent development of probable Alzheimer disease (pAD) and to identify the pattern of earliest changes in cognitive functioning associated with a diagnosis of pAD. From May 1975 to November 1979, a screening neuropsychological battery was administered to Framingham Study participants. They were followed up prospectively for 22 years and examined at least every 2 years for the development of pAD. A community-based center for epidemiological research. Subjects were 1076 participants of the Framingham Study aged 65 to 94 years who were free of dementia and stroke at baseline (initial) neuropsychological testing. Presence or absence of pAD during a 22-year surveillance period was related to test performance at initial neuropsychological testing. Lower scores for measures of new learning, recall, retention, and abstract reasoning obtained during a dementia-free period were associated with the development of pAD. Lower scores for measures of abstract reasoning and retention predicted pAD after a dementia-free period of 10 years. The "preclinical phase" of detectable lowering of cognitive functioning precedes the appearance of pAD by many years. Measures of retention of information and abstract reasoning are among the strongest predictors of pAD when the interval between initial assessment and the development of pAD is long. Arch Neurol. 2000.
Article
A prospective analysis of risk factors for Alzheimer's disease was a major objective of the Canadian Study of Health and Aging, a nationwide, population-based study. Of 6,434 eligible subjects aged 65 years or older in 1991, 4,615 were alive in 1996 and participated in the follow-up study. All participants were cognitively normal in 1991 when they completed a risk factor questionnaire. Their cognitive status was reassessed 5 years later by using a similar two-phase procedure, including a screening interview, followed by a clinical examination when indicated. The analysis included 194 Alzheimer's disease cases and 3,894 cognitively normal controls. Increasing age, fewer years of education, and the apolipoprotein E epsilon4 allele were significantly associated with increased risk of Alzheimer's disease. Use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimer's disease. No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, smoking, high blood pressure, heart disease, or stroke. The protective associations warrant further study. In particular, regular physical activity could be an important component of a preventive strategy against Alzheimer's disease and many other conditions.
Article
The hygiene hypothesis postulates that an environment with a high incidence of infectious diseases protects against allergic and autoimmune diseases, whereas hygienic surroundings increase the incidence of these disorders. This review examines the evidence in support of the hygiene hypothesis and offers a number of mechanisms that could explain the relation between sanitary conditions and susceptibility to allergic and autoimmune diseases.
Article
The catastrophic loss of cerebral neurons in Alzheimer's disease (AD) is not fully understood. Since serum proteins are known to extravasate into the brain parenchyma in AD due to blood-brain barrier (BBB) dysfunction, this study was designed to explore the possibility that neuronal cell death may be the consequence of the anomalous presence of serum proteins in the brain. As compared to age-matched, non-demented 'control' brain tissues, highly significant increases of immunoglobulins (Igs) were detected in parenchyma, which were associated with vessels in the AD brain tissues. Also, there were dramatic increases of +Ig-neurons in areas with greater parenchymal Ig reactivity. The Ig labeling extended throughout the cell, which showed neurodegenerative apoptotic features that were not observed in -Ig-neurons. Thus, the presence of +Ig-neurons in AD brains implies a critical link between the faulty BBB and neuronal death through an autoimmune mechanism.
Article
Alzheimer disease (AD) involves glial inflammation associated with amyloid plaques. The role of the microglial cells in the AD brain is controversial, as it remains unclear if the microglia form the amyloid fibrils of plaques or react to them in a macrophage-phagocytic role. Also, it is not known why microglia are preferentially associated with some amyloid plaque types. This review will provide substantial evidence to support the phagocytic role of microglia in the brain as well as explain why microglia are generally associated with specific plaque types that may be explained through their unique mechanisms of formation. In summary, the data presented suggests that plaque associated microglial activation is typically subsequent to specific amyloid plaque formations in the AD brain.
Article
A sole pathological event leading to Alzheimer's disease (AD) remains undiscovered in spite of decades of costly research. In fact, it is more probable that the causes of AD are the result of a myriad of intertwining pathologies. However, hope remains that a single awry event could lead to the many pathological events observed in AD brain tissues thereby creating the presentation of simultaneous pathologies. Age-related vascular diseases, which include an impaired blood-brain barrier (BBB), are a common denominator associated with various degrees of dementia, including AD. Recently, a key finding not only demonstrated the anomalous presence of immunoglobulin (Ig) detection in the brain parenchyma of AD tissues but, most importantly, specific neurons that showed degenerative, apoptotic features contained these vascular-derived antibodies. In addition, subsequent studies detected classical complement components, C1q and C5b-9, in these Ig-positive neurons, which also were spatially more associated with reactive microglia over the Ig-negative neurons. Thus, it is possible that the mere presence of anti-neuronal autoantibodies in the serum, whose importance had been previously dismissed, may be without pathological consequence until there is a BBB dysfunction to allow the deleterious effects of these autoantibodies access on their targets. Hence, these observations suggest autoimmunity-induced cell death in AD.
Article
A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.
Article
To determine the roles of blood-brain barrier (BBB) transport and plasma protein binding in brain uptake of nonsteroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, and indomethacin. Brain uptake was measured using in situ rat brain perfusion technique. [14C]Ibuprofen, [3H]flurbiprofen, and [14C]indomethacin were rapidly taken up into the brain in the absence of plasma protein with BBB permeability-surface area products (PS(u)) to free drug of (2.63 +/- 0.11) x 10(-2), (1.60 +/- 0.08) x 10(-2), and (0.64 +/- 0.05) x 10(-2) mL s(-1) g(-1) (n = 9-11), respectively. BBB [14C]ibuprofen uptake was inhibited by unlabeled ibuprofen (Km = 0.85 +/- 0.02 mM, Vmax = 13.5 +/- 0.4 nmol s(-1) g(-1)) and indomethacin, but not by pyruvate, probenecid, digoxin, or valproate. No evidence was found for saturable BBB uptake of [3H]flurbiprofen or [14C]indomethacin. Initial brain uptake for all three NSAIDs was reduced by the addition of albumin to the perfusion buffer. The magnitude of the brain uptake reduction correlated with the NSAID free fraction in the perfusate. Free ibuprofen, flurbiprofen, and indomethacin rapidly cross the BBB, with ibuprofen exhibiting a saturable component of transport. Plasma protein binding limits brain NSAID uptake by reducing the free fraction of NSAID in the circulation.
Article
For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the "null hypothesis." Indeed, amyloid-beta is, by the current definition of the disease, an obligate player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta is the focus of considerable basic and therapeutic interest. However, an increasingly vocal group of investigators are arriving at an "alternate hypothesis" stating that amyloid-beta, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is not as a harbinger of death but rather a protective response to neuronal insult. To determine which hypothesis relates best to Alzheimer disease requires a broader view of disease pathogenesis and is discussed herein.
Article
Understanding of autoimmune diseases, including multiple sclerosis, has expanded considerably in recent years. New insights have been provided by not only animal models but also studies of patients, often in conjunction with experimental therapies. It is accepted that autoimmune T cells mediate the early steps of new multiple sclerosis lesions, and although uncertainties remain about the specific targets of autoreactive T cells, several studies indicate myelin antigens. Recent findings obtained with both animal models and patients with multiple sclerosis indicate involvement of a T helper cell with a T(H)-17 phenotype, in contrast to previous data indicating that T helper type 1 cells are critical. Evidence has also been presented for CD8(+) and regulatory T cell populations, although their involvement remains to be established. Despite evidence supporting the idea that autoreactive T cells are involved in disease induction, cells of myeloid lineage, antibodies and complement as well as processes intrinsic to the central nervous system seem to determine the effector stages of tissue damage. Careful analysis of the alterations in immune processes should further advance knowledge of the relationship between the inflammatory component of this disease and the more diffuse degeneration of progressive multiple sclerosis.
Article
To examine the association between number of born children and neuropathology of Alzheimer's disease (AD). The brains of 86 subjects with data on the number of biological children born, were studied postmortem. Primary analyses included 73 subjects (average age at death=80; 42 women) devoid of cerebrovascular disease associated lesions (i.e., infarcts) or of non-AD related neuropathology. Women were significantly older at death than men (85.6 vs. 73.4; p<.0005) but did not differ significantly from men in number of children or dementia severity. Secondary analyses included 13 additional subjects who had concomitant cerebrovascular disease. Density of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the hippocampus, entorhinal cortex, amygdala and multiple regions of the cerebral cortex, as well as composites of these indices reflecting overall neuropathology, were analyzed. For men and women separately, partial correlations, controlling for age at death and dementia severity, were used to assess the associations of number of children with these neuropathological variables. Among women, all the partial correlations were positive, with statistical significance for overall neuropathology (r=.37; p=.02), overall NPs (r=.36; p=.02), and for NPs in the amygdala (r=.47; p=.002). Among men, none of the partial correlations were statistically significant. Results of the secondary analyses were similar. Since the associations between number of children and neuropathology of AD were found for women only, they might reflect sex-specific mechanisms (such as variations in estrogen or luteinizing hormone levels) rather than social, economic, biological or other mechanisms common to both men and women.