Neuropsychiatric illness, autoimmunity and the role of microbes

Current Opinion in RheumatologyNeuropsychiatric illness often involves brain inflammation for which there may be an autoimmune origin. The authors of a paper* recently published in Current Opinion in Rheumatology set out to…

“…illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets.”

They describe the science emerging on underlying mechanisms behind the observations that both exposure to infectious agents and autoantibodies without evidence of pathogens can cause brain disorders…

“…….evidence accumulates to support the idea that dysregulated cross-talk between the brain and the immune system is an important contributor to the pathogenesis of conditions as diverse as schizophrenia, mood disorders, autism spectrum disorders (ASDs), obsessive-compulsive disorder (OCD), Tourette syndrome and other tic disorders, attention-deficit hyperactivity disorder (ADHD), anorexia nervosa, narcolepsy, posttraumatic stress disorder and myalgic encephalomyelitis/chronic fatigue syndrome (CFS). In addition, intriguing new evidence lends support to the possibility that not only the microbes associated with infectious episodes but also the bacteria of the gut microbiome can foster the production of brain-reactive autoantibodies, and that these microbe-induced antibodies provide the critical link between infection and neuropsychiatric disorders.”

In the case of infection, it may not even matter so much what the infectious agent is…

“A complication in delineating the relationship of a particular pathogen to a particular neuropsychiatric disorder is that even if the link is real, it may nonetheless be nonspecific, both in terms of the type of infectious agent capable of inducing brain dysfunction, as well as in the neurobehavioral features that follow. An expanding body of studies using animal models of infection-related developmental disorders reports persistent effects on offspring brain development and behavior following prenatal or early postnatal exposures to noninfectious agents that mimic actual infection with influenza virus, such as polyinosinic:polycytidylic acid (poly I:C, a form of synthetic, double-stranded RNA), or a bacterium, such as lipopolysaccharide (LPS, or bacterial endotoxin), illustrating the importance of maternal immune responses as modifiers of postinfectious sequelae in the offspring. Findings from these studies suggest that CNS damage requires the presence of innate immune and inflammatory molecules that disrupt brain development.”

Noting that shifts in maternal immune activation toward an autoimmune and allergic phenotype predisposed offspring to autism-like behaviors which were subsequently abolished by bone marrow transplantation to modify immune expression…

“In addition to this overlap in neurodevelopmental consequences after prenatal and postnatal virus-like and bacteria-like exposures, exposure of infant mice to environmental contaminants such as the organic compound, toluene, is associated with upregulated expression of cytokine genes in hippocampus. Thus, increasing evidence suggests that it is the presence of innate immune molecules, as opposed to direct infection of neurons and glial cells, that mediates these effects.”

While breaching of the blood brain barrier (BBB) immunoreactive agents into the privileged space of the central nervous system, it may not always be necessary for the manifestation of neuropsychiatric symptoms:

“Another study that focused on GAS [group A streptococcus]-related, CNS-directed autoimmunity raised the intriguing suggestion that alternate transport systems may exist for entry of certain immunoglobulin isotypes or subclasses into the CNS. Zhang et al. injected naïve mice with anti-GAS IgM monoclonal antibodies, without the use of an adjuvant to breach the BBB, and found increased stereotypic behaviors…Transcellular mechanisms that obviated the need to compromise BBB integrity were postulated to facilitate the entry of these IgM antibodies into the CNS.”

Pathogens aren’t the only microbes that can incite autoimmune activity. As noted in earlier posts, the ‘normal’ commensal microbiota can also participate in loss of immune tolerance:

“Recent evidence suggests that both pathogenic and commensal microbes play a role in the pathogenesis of a subset of neuropsychiatric disorders through induction of brain-reactive autoantibodies. Whereas infection with certain pathogens can trigger autoantibody production through molecular mimicry, commensal bacteria that comprise the gastrointestinal microbiota probably set the stage for the development of autoimmune responses by skewing immune responses toward overproduction of Th17 cells and reduction in numbers and function of Tregs.”

The authors also note the role of antioxidants and depletion of the antoxidant system, particularly glutathione:

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Increased oxidative stress with diminished glutathione impairs Tregs, increasing autoimmunity.

Failed uptake of antioxidant precursors in the terminal ileum, influenced by differences in tryptophan degradation capacity of the microbiota and related factors, may also contribute to a skew toward autoimmunity by reducing levels of Tregs and increasing levels of autoimmunity-provoking Th17 cells.”

The link between schizophrenia and Toxoplasma gondii infection is illustrative:

“There is also evidence that the microbial infection itself is not likely to be as important in pathogenesis as the presence of antibodies to the microbe, as well as the isotype and binding characteristics (cross-reactivity, affinity and avidity) of these antibodies. Anti-toxoplasma antibodies may also be more prevalent in individuals with bipolar disorder, type 1.”


“In individuals with schizophrenia, antibodies directed against food antigens, including bovine milk casein and wheat-derived gluten, are correlated with the presence of antibodies to T. gondii…In a separate study, increased levels of anti-gliadin antibodies were found in individuals with schizophrenia. Furthermore, the interactomes of nine neuropsychiatric disorders, including multiple sclerosis, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson’s disease, ADHD and ASD, but not anorexia nervosa or myalgic encephalomyelitis/CFS, showed significant overlap with the interactome of T. gondii, and has been closely associated with a number of autoimmune diseases.”

Interestingly, autoimmunity with loss of tolerance to gluten may involve reduced antioxidant capacity:

“The relationship of anti-toxoplasma antibodies to anti-gliadin antibodies in some neuropsychiatric disorders may relate to reduced antioxidant capacity in the terminal ileum. Gliadin, a major protein component of wheat that is associated with celiac disease, also appears able to dysregulate redox balance in peripheral blood mononuclear cells, triggering allergic-type responses that include specific enhancement of IL-4-mediated IgE production…A clearer understanding of these processes may uncover unique strategies for intervention with less potential for toxicity, including antioxidants, prebiotics, probiotics and transplantation of fecal microbiota.”

Clinical note: Clearly practitioners must be alert to the role of autoimmunity in neuropsychiatric disorders and must discriminate between infection and loss of immune tolerance triggered by infection. It may not be so apparent that the indigenous commensal microbiota can play a role in autoimmunity, antimicrobial therapy may modify symptoms for a time but ‘dig the hole deeper’, and that caution must be observed in contemplating treatment for infections that expose the immune system to the lipopolysaccharides of disintegrating bacterial and fungal cells in the presence of active or latent loss of immune tolerance.

The authors conclude:

“Genetically susceptible individuals may generate brain-reactive autoantibodies when exposed to certain infectious agents or commensal organisms. Under inflammatory conditions that promote BBB disruption and facilitate trafficking into the CNS, binding of autoantibodies to cross-reactive epitopes may contribute to the cognitive and behavioral disturbances associated with these disorders by altering brain activity within key circuitry. This conceptual model views altered brain–immune signaling as a product of the interaction of immune response genes and microbial exposures at key points during prenatal and postnatal development, and provides a framework within which discordant findings across studies of different neuropsychiatric disorders may be better explained and through which novel pathways for improved therapeutics may be discovered.”

* The entire paper can be read in Medscape Family Medicine.

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The advantages of intermittent versus continuous calorie restriction for long term weight loss

There is an accumulation of fascinating scientific evidence that intermittent calorie restriction (ICR) offers a number of advantages over continuous calorie restriction (CCR) for successful long term weight loss and the ‘turning on’ of genes that favor longevity. Consider a study published recently in the International Journal of Obesity in which the investigators compared ICR and CCR for weight loss and metabolic disease risk markers in overweight women. The authors state:

“Excess weight and weight gain during adult life increases the risk of several diseases including diabetes, cardiovascular disease (CVD), dementia, certain forms of cancer including breast cancer, and can contribute to premature death. Observational and some randomised trials indicate that modest weight reduction (>5% of body weight) reduces the incidence and progression of many of these diseases. Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known.”


“Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation. Sustainable and effective energy restriction strategies are thus required.”

In other words, a method that can be comfortable enough to be accepted into daily life for the long that also avoids loss of improvements due to adaption is required.

“One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction.”

So the authors set out to…

“…compare the feasibility and effectiveness of IER with CER for weight loss, insulin sensitivity and other metabolic disease risk markers…This is the largest randomised comparison of an isocalorific intermittent vs. continuous energy restriction to date in free living humans..”

They designed a randomised comparison of a 25% energy restriction as IER (~2266 kJ/day which equals 541 calories per day for 2 days/week) or CER (~6276 kJ/day equaling 1499 calories each day for 7 days/week) in 107 overweight or obese premenopausal women for a 6 month study period. They measured an extensive list of biomarkers at baseline and after 1, 3 and 6 months: weight, anthropometry (size, weight and proportions), biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, IGF-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain derived neurotrophic factor. What did the data show?

“Last observation carried forward analysis showed IER and CER are equally effective for weight loss, mean weight change for IER was −6.4 kg vs. −5.6 kg for CER. Both groups experienced comparable reductions in leptin, free androgen index, high sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than CER; difference between groups for fasting insulin −1.2 μU/ml, and insulin resistance −1.2 μU/mmol/L.”

Regarding concerns about tolerance…

“A recent blinded trial of a 2 day VLCD [very low calorie diet] (1311 kJ/day [313 calories per day!]) reported no adverse effects on cognition, energy levels, sleep or mood, suggesting symptoms are expected with VLCD and therefore experienced and could potentially be overcome with appropriate counselling. Importantly IER did not lead to overeating on non-VLCD days.”

The authors briefly summarize the results of their comparison of IER and CER by concluding:

IER is as effective as CER in regards to weight loss, insulin sensitivity and other health biomarkers and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.”

That’s not all though. The authors additionally note an extremely interesting observation with profound implications and potential for benefit regarding additional benefits of an intermittent very low calorie method:

“Recent reviews speculate that IER may be associated with greater disease prevention than CER due to increased cellular stress resistance, in particular increased resistance to oxidative stress. This is thought to be mediated by ‘hormesis’ whereby the moderate stress of energy restriction increases the production of cytoprotective, restorative proteins, antioxidant enzymes and protein chaperones. Alternate day fasting has been linked to increased SIRT-1 gene expression in muscle, and to greater neuronal resistance to injury compared to CER in C57BL/6 mice. The tendency for greater improvements in oxidative stress markers in our IER than in the CER group may support these assertions. Declines in long term protein oxidation product aggregates suggest IER as a possible activator of catabolism and autophagy.”

In other words, intermittent calorie restriction can be as effective as continuous calorie restriction for weight loss, but have the added advantage of ‘turning on’ genes beneficial for health and longevity and preventing adaptation that would result in regaining weight.

Other investigators also have compared intermittent with continuous calorie (daily) calorie restriction as in a study published recently in the journal Obesity Reviews. The authors set out to…

“…evaluate and compare the effects of daily CR versus intermittent CR on weight loss, fat mass loss, lean mass retention and visceral fat mass reduction, in overweight and obese adults.”

They undertook a review of studies that were randomized control trials, had a primary endpoint of weight loss and/or body composition changes, used daily CR or intermittent CR as the primary focus of the intervention; had a study duration of 4–24 weeks, and involved adult populations who were overweight or obese subjects but not diabetic. These included 11 daily continuous calorie restriction trials and five intermittent CR trials published between 2000 and 2010, along with two unpublished trials of intermittent CR from their own lab. What did all these studies add up to?

“Results reveal similar weight loss and fat mass loss with 3 to 12 weeks’ intermittent CR (4–8%, 11–16%, respectively) and daily CR (5–8%, 10–20%, respectively). In contrast, less fat free mass was lost in response to intermittent CR versus daily CR.”

This is a significant advantage of ICR over CCR (continuous = daily calorie restriction). The authors conclude by stating:

“In sum, intermittent CR and daily CR diets appear to be equally as effective in decreasing body weight, fat mass, and potentially, visceral fat mass. However, intermittent restriction regimens may be superior to daily restriction regimens in that they help conserve lean mass at the expense of fat mass. These findings add to the growing body of evidence showing that intermittent CR may be implemented as another viable option for weight loss in overweight and obese populations.”

Numerous other studies have examined the distinctive benefits of intermittent calorie restriction. A paper published recently in the journal Oncogene investigates the positive effects of brief ICR compared to CCR for cancer patients. The authors state:

“The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels.”

They point out that cancer cells are unable to respond to the positive stimuli of calorie restriction:

“Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells.”


“Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans.”

They go on to review studies on fasting, cellular protection and chemotherapy resistance, and futher compare them to those on continuous calorie restriction and cancer treatment. The authors conclude:

“Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.”

A study published in the Journal of Molecular and Cellular Cardiology offers evidence that intermittent calorie restriction activates genes that help in the recovery from heart damage. The authors state:

Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI).

Two weeks after myocardial ischemia was induced in their study animals, they were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks the authors evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival. The results were truly striking:

Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4 ± 0.17 versus 3.9 ± 0.18. Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group. Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-α (3010 ± 350% versus 650 ± 151%), BDNF (523 ± 32% versus 110 ± 12%), and VEGF (450 ± 21% versus 170 ± 30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone.”

This is a dramatic indication that intermittent calorie restriction can be used to protect and repair heart tissue. The authors conclude:

Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.”

Another fascinating study published recently in the journal Cancer Prevention Research demonstrates that intermittent calorie restriction is clearly superior to both continuous calorie restriction and an unrestricted diet for breast cancer prevention. Specifically, the authors studied…

“The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels…in relation to mammary tumorigenesis.”

Their subjects were assigned to ad libitum fed, ICR (3-week 50% caloric restriction followed by 3-wks 100% AL consumption), and CCR groups.

Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad.”

This amounts to an impressive ‘turning on’ of genes that protect against breast cancer for ICR. In conclusion…

“…we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.”

A paper published in the journal Nutrition and Cancer demonstrates that ICR offers a greater protective effect than CCR for prostate cancer. The authors state:

“Prostate cancer is the most frequently diagnosed cancer in men. Whereas chronic calorie restriction (CCR) delays prostate tumorigenesis in some rodent models, the impact of intermittent caloric restriction (ICR) has not been determined. Here, transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were used to compare how ICR and CCR affected prostate cancer development.”

Their animal models for prostate cancer were assigned to ad libitum (AL), ICR, and CCR groups. There were distinctive differences according to the manner of calorie restriction that dramatically favored the ICR over both the AL and CCR cohorts:

“ICR mice were older at tumor detection than AL and CCR mice. There was no difference for age of tumor detection between AL and CCR mice. Similar results were found for survival. Serum leptin, adiponectin, insulin, and IGF-I were all significantly different among the groups.”

Not only did the subjects on CCR live longer with healthier biomarkers than the ones on either the free diet or CCR, there was no difference between the AL and CCR groups for age of tumor detection or survival. The implication is exciting: the benefits were due not to the weight loss component but to the way in which ICR affects gene expression. The authors conclude:

“These results indicate that the way in which calories are restricted impacts both time to tumor detection and survival in TRAMP mice, with ICR providing greater protective effect compared to CCR.”

A paper published in the The Journal of Nutritional Biochemistry also offers evidence that intermittent calorie restriction protects heart tissue:

“It has been reported that dietary energy restriction, including intermittent fasting (IF), can protect heart and brain cells against injury and improve functional outcome in animal models of myocardial infarction (MI) and stroke. Here we report that IF improves glycemic control and protects the myocardium against ischemia-induced cell damage and inflammation in rats.”

The authors showed by echocardiographic analysis of heart structur and function that intermittent fasting attenuates the disease related increase in heart thickness, end systolic and diastolic volumes, and ejection fraction. Additionally…

“The size of the ischemic infarct 24 h following permanent ligation of a coronary artery was significantly smaller, and markers of inflammation (infiltration of leukocytes in the area at risk and plasma IL-6 levels) were less, in IF rats compared to rats on the control diet. IF resulted in increased levels of circulating adiponectin prior to and after MI.”

There is now a large body of evidence showing that ICR increases the protective hormone adiponectin much more than CCR. The authors conclude:

“Because recent studies have shown that adiponectin can protect the heart against ischemic injury, our findings suggest a potential role for adiponectin as a mediator of the cardioprotective effect of IF.”

A paper published in the journal Ageing Research Reviews discusses how IFR and CCR can protect the brain from accelerated neurodegeneration associated with aging. The authors note:

“The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span.”

As we’ve seen regarding cardioprotection and tumorigenesis…

“CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease.”

These studies comprise the first post that illustrates the scientific basis for the Lapis Light Weight Loss & Gene Modulation Program that customizes intermittent calorie restriction according to the individual’s weight management and other health needs. Subsequent posts will offer additional scientific evidence important for other aspects of the program.

Vitamin D for cognitive decline and Parkinson’s Disease

Archives of Internal MedicineTwo studies have just been published linking Vitamin D status to brain health. The authors of one paper appearing in Archives of Internal Medicine observe:

“To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia.”

They examined the correlation between low levels of serum 25-hydroxyvitamin D (25[OH]D) and the risk of serious loss of cognitive function in 858 adults over 8 years. What did the data show?

“…substantial cognitive decline on the MMSE [Mini-Mental State Examination] in participants who were severely serum 25(OH)D deficient (levels <25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (≥75 nmol/L)…the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D.”

Thus their conclusion:

Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.”

Archives of NeurologyThe same week a study was published in Archives of Neurology that examines the relation between Vitamin D and Parkinson Disease. The authors set out to:

“…investigate whether serum vitamin D level predicts the risk of Parkinson disease.”

They crunched the numbers for 3,173 men and women who were followed up over 29 years (the baseline serum 25-hydroxyvitamin D level was determined from frozen samples) for the relationship between serum vitamin D concentration and Parkinson disease. The data showed that:

Individuals with higher serum vitamin D concentrations showed a reduced risk of Parkinson disease. The relative risk between the highest and lowest quartiles was 0.33 [about a third less] after adjustment for sex, age, marital status, education, alcohol consumption, leisure-time physical activity, smoking, body mass index, and month of blood draw.”

Thus their conclusion:

“The results are consistent with the suggestion that high vitamin D status provides protection against Parkinson disease.”

The results of these studies are not surprising considering that Vitamin D is necessary for regulating the immune inflammatory response and both dementia and Parkinson’s involve chronic brain inflammation. By the way, as stated in Science Insider:

“Most Alzheimer’s disease (AD) researchers agree that the disease starts ravaging the brain years, if not decades, before the first symptoms of forgetfulness appear.”

New diagnostic criteria were just proposed at the International Conference on Alzheimer’s Disease in Honolulu.

Loss of smell can be an early sign of Parkinson’s Disease

European Human Genetics ConferenceThe sooner we recognize signs of neurodegeneration and intervene to reduce the underlying causes the better. A valuable presentation was offered at the recent European Human Genetics Conference 2010 describing research advancing the early diagnosis of Parkinson’s Disease.

“Dr. Nuber and colleagues from Germany, Switzerland, and the UK, decided to study transgenic mice with high levels of human alpha-synuclein, a protein known to be crucial in the development of PD…“The mice expressed alpha-synuclein primarily in neurons of the olfactory bulb”, said Dr. Nuber, “and we therefore expected to find alterations in smell-related behaviour in these animals. Since one of the earliest symptoms in PD patients is a reduction in the sense of smell, we felt that these mice could mimic the early stages of the disease.””

Abnormal dopamine signaling is a fundamental characteristic of Parkinson’s Disease. The investigators demonstrated that impairment of dopamine function in olfactory pathways was apparent well before degradation of motor control.

“The nigrostriatal pathway is one of the major dopamine pathways in the brain, and is particularly involved in the control of movements. Loss of dopaminergic neurons in the substantia nigra, a structure located in the midbrain, is one of the main features of PD, but the motor symptoms of the disease do not show themselves until more than half of the dopamine function has been lost. Being able to identify the early stages of dopaminergic dysfunction is therefore particularly important both for diagnosis and treatment of PD.”

They studied transgenic mice with high levels of human alpha-synuclein, a substance that accumulates in PD.

“The mice expressed alpha-synuclein primarily in neurons of the olfactory bulb”, said Dr. Nuber, “and we therefore expected to find alterations in smell-related behaviour in these animals. Since one of the earliest symptoms in PD patients is a reduction in the sense of smell, we felt that these mice could mimic the early stages of the disease.”

Having resolved the mechanism by which smell is impaired at an early stage of PD…

“The researchers say that it would be worthwhile to develop some standardised tests for testing smell function. “Based on what we know now, the clinical definition for the diagnosis of PD should not rely solely on the diagnosis of motor symptoms. It would be helpful to test the ability of olfactory detection and learning.”

Of course PD or other expressions of accelerated neurodegeneration are not the only causes of impaired smell. But because it is so important to protect against loss of brain health before it advances, be aware that diminished function of any of the senses can be similar to declining memory and motor function in their implications.

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Adolescence, a dangerous time for alcohol excess—but so is anytime

Proceedings of the National AcademyAdding more concern to the reported increase in heavy alcohol consumption among adolescents is the emerging science regarding alcohol’s effect on the brain. This research just published in the Proceedings of the National Academy of Sciences elucidates the mechanism by which binge drinking damages the developing brain.

“Binge alcohol consumption in adolescents is increasing, and studies in animal models show that adolescence is a period of high vulnerability to brain insults. The purpose of the present study was to determine the deleterious effects of binge alcohol on hippocampal neurogenesis…”

The authors made a number of startling observations regarding the effect of alcohol on the brain’s center for short-term memory and adrenal regulation, the hippocampus:

“Heavy binge alcohol consumption over 11 mo dramatically and persistently decreased hippocampal proliferation and neurogenesis…Alcohol significantly decreased the number of actively dividing type 1, 2a, and 2b cell types…suggesting that alcohol interferes with the division and migration of hippocampal preneuronal progenitors. Furthermore, the lasting alcohol-induced reduction in hippocampal neurogenesis paralleled an increase in neural degeneration mediated by nonapoptotic pathways.”

Yikes. The authors sum up their findings with these memorable comments:

“Altogether, these results demonstrate that the hippocampal neurogenic niche during adolescence is highly vulnerable to alcoholThis lasting effect, observed 2 mo after alcohol discontinuation, may underlie the deficits in hippocampus-associated cognitive tasks that are observed in alcoholics.”

Journal of NeuroscienceA fascinating paper published last month in the Journal of Neuroscience now reveals how alcohol feeds an immune inflammatory attack on the brain:

Toll-like receptors play an important role in the innate immune response, although emerging evidence indicates their role in brain injury and neurodegeneration. Alcohol abuse induces brain damage and can sometimes lead to neurodegeneration. We recently found that ethanol can promote TLR4 signaling in glial cells by triggering the induction of inflammatory mediators and causing cell death, suggesting that the TLR4 response could be an important mechanism of ethanol-induced neuroinflammation.”

This is an extremely persuasive argument for moderation for anyone interesting in preserving brain health.

The authors go on to report that TLR4 is critical for ethanol-induced inflammatory signaling in glial cells by demonstrating that ‘turning off’ TLR4 prevents the neuroinflammatory brain damage:

“Our results demonstrate, for the first time, that whereas chronic ethanol intake upregulates…cytokine levels [interleukin (IL)-1β, tumor necrosis factor-{alpha}, IL-6] in the cerebral cortex,…TLR4 deficiency protects against ethanol-induced glial activation, induction of inflammatory mediators, and apoptosis. Our findings support the critical role of the TLR4 response in the neuroinflammation, brain injury, and possibly in the neurodegeneration induced by chronic ethanol intake.”

Science Translational Medicine 0710For us the main message is that excessive alcohol consumption fires up the brain’s glial cells (immune cells) and the resultant neuroinflammation does serious damage to the brain. This important research was highlighted in an editorial published last week in Science Translational Medicine which contains some notable comments:

“Ethanol is the most widely used psychotropic substance in the world, and chronic ethanol abuse leads to harmful changes in virtually every organ system in the body. Notably, this includes the brain, where consumption of alcohol can lead to irreversible changes in cognition, mood, and behavior. Although it has been known that this often involves degenerative, inflammatory-mediated processes, their precise nature has not been characterized. In a recent article, Alfonso-Loeches and colleagues report that much of the ethanol-induced inflammation in the brain depends on signaling through Toll-like receptors (TLRs). These receptors participate in innate immunity responses to infection but are also implicated in reactions to injury and degeneration in the brain.”

The editorial concludes with the compelling comparison of the brain damage done by activation by alcohol of neuroinflammation through Toll-like receptors with other common neurodegenerative conditions:

“These results suggest that TLRs play a critical role in alcohol-related brain changes, just as they have been previously implicated in Alzheimer’s disease, ischemic brain injury, and HIV infection.”

Inflammation ResearchBesides curtailing excess and enjoying alcohol only in moderation we may be able to use coffee as protective therapy. There is abundant evidence of the benefit of coffee for the liver, including this recent study published in the journal Inflammation Research. The authors present data that:

“Treatment with caffeine significantly attenuated the elevated serum aminotransferase enzymes and reduced the severe extent of hepatic cell damage, steatosis and the immigration of inflammatory cells… Furthermore, caffeine decreased serum and tissue inflammatory cytokines levels, tissue lipid peroxidation and inhibited the necrosis of hepatocytes. Kupffer cells isolated from ethanol-fed mice produced high amounts of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α), whereas Kupffer cells from caffeine treatment mice produced less ROS and TNF-α.”

The authors conclude:

“These findings suggest that caffeine may represent a novel, protective strategy against alcoholic liver injury by attenuating oxidative stress and inflammatory response.”

Experimental NeurologyCould this protective effect extend to the brain? There’s a lot of emerging evidence that suggests the answer is ‘yes’. Fascinating research published last month in the journal Experimental Neurology demonstrates that caffeine protects the brain from the kind of damage involved in Parkinson’s disease caused by pesticides:

“Environmental exposures suspected of contributing to the pathophysiology of Parkinson’s disease (PD) include potentially neurotoxic pesticides, which have been linked to an increased risk of PD. Conversely, possible protective factors such as…caffeine have been linked to a reduced risk of the disease. Here we assessed whether caffeine alters dopaminergic neuron loss induced by exposure to environmentally relevant pesticides (paraquat and maneb) over 8 weeks.”

The data led to a conclusion that increases my enthusiasm for exercising the French press:

Caffeine at 20 mg/kg significantly reduced TH+ neuron loss (to 85% of the respective control). The results demonstrate the neuroprotective potential of caffeine in a chronic pesticide exposure model of model of PD.”

Journal of Alzheimer's DiseaseAs for Alzheimer’s disease, a supplemental issue of the Journal of Alzheimer’s Disease has no less than 22 papers on the benefits of caffeine for AD and other neurodegenerative disorders. I suggest you have a look, drink alcohol in moderation (or not at all if you prefer), and enjoy your coffee and tea if there are no contraindications.

With alcohol, as with so many other substances and stimuli, we can appreciate the principle of hormesis: a small amount may have benefit while a larger amount is harmful.

Neuroinflammation plays a crucial role in neurodegenerative diseases

Molecular NeurodegenerationThis excellent review published recently in the journal Molecular Neurodegeneration elucidates the epidemiologic, pharmacologic and genetic evidence that explains why inflammation in the brain and the rest of the central nervous system is a key factor in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis.

“While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults.”

Inflammatory stimuli include allergens (gluten, etc.), infections, trauma, neurogenic activation of the inflammatory response, and others. Microglia (the immune cells in the brain) are activated and release inflammatory mediators, the cytokines and chemokines that we measure with lab tests.

“…chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult.”

Once chronic neuroinflammation has been established, these inflammatory mediators perpetuate a cascading inflammatory cycle.

Neuroinflammation, neuronal dysfunction and degeneration

Neuroinflammation, neuronal dysfunction and degeneration

“Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines.”

In other words, microglial activation and the chronic inflammation it perpetuates is the convergence point for all the kinds of stimuli associated with these neurodegenerative disorders as well as many other conditions affected by compromised brain function. This is partly why it is of such great practical importance to profile immune dysregulation in the central nervous system with the appropriate lab tests as a basis for rational therapy.