“Repeated immunization with antigen causes systemic autoimmunity… Overstimulation of CD4+ T cells led to the development of autoantibody-inducing CD4+ T (aiCD4+ T) cell[s]…[which became] antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE).”

This essentially means that overexposure to a potential antigen (increased amounts of gluten in hybridized wheat, higher environmental levels of mercury, etc.) can result in sensitization of the immune system with cross-reaction to our own tissues (autoimmune disease). The authors clearly state their conclusion drawn from the evidence:

“Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host’s immune ‘system’ by repeated immunization with antigen, to the levels that surpass system’s self-organized criticality.”

GAD (glutamic acid decarboxylase) antibodies

“The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases.”

They used ELISA assays for GAD antibodies and serological markers of gluten sensitivity that generated compelling data:

“”Six of seven (86%) patients with SPS were positive for anti-GAD…This compared with 9/90 (11%) patients with idiopathic sporadic ataxia…16/40 (40%) patients with gluten ataxia…and 6/10 patients with type 1 diabetes only…”

Note that the serological tests for gluten sensitivity are a blunt instrument—only 40% of confirmed cases of gluten ataxia were recognized. The abundance of false negatives is why the gluten gene sensitivity test is so valuable.

Additionally, the authors found that…

“The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity.”

Their conclusion is simply stated:

“These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases.“

This study is especially interesting in connection with earlier research published in the journal Psychiatry. The authors set out to investigate the role of GAD antibodies in schizophrenia and related disorders:

“We hypothesized that GAD antibodies are increased in patients with chronic psychotic disorders. The aim of this pilot study was to compare the level of GAD antibodies in patients with chronic psychotic disorders with normal controls.”

By way of background they note that:

“The role of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, and premenstrual dysphoric disorder has been a subject of some recent investigations. Absence of structural abnormalities in the brains of most patients with chronic psychotic disorders has always raised suspicion for an alternative pathogenesis and a possible functional disturbance at the neuronal/cellular level. Glutamic acid decarboxylase (GAD)…is involved in the formation of gamma aminobutyric acid (GABA) a central inhibitory neurotransmitter of the nervous system. Antibodies to GAD may impair GABA formation or inhibitory function.“

What did the data show?

“Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated… Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals.”

The authors’ conclusion alerts the practitioner to be on the lookout:

“Antibodies to GAD65 are peripherally present in patients with chronic psychotic disorders (schizophrenia/schizoaffective disorders)... The presence of such antibodies also suggests a possible role for autoimmune mechanism in the pathogenesis of these disorders. In summary, from a practicing psychiatrist’s point of view, measurements of antibodies to GAD65 could potentially be used to screen for chronic psychotic disorders and for diabetes mellitus very early on in the disease process.”

GAD (glutamic acid decarboxylase) produces GABA, the most abundant inhibitory (calming) neurotransmitter in the body. Suboptimal levels can manifest as anxiety, insomnia, hyperarousal, panic, feeling overwhelmed, disorganized attention, restlessness, worry, tension, inner excitability, inability to relax, etc.

“A higher insulin level has been linked to the risk of prostate cancer promotion…the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder.”

They proceeded by following 389 patients who had lower urinary tract symptoms without prostate cancer over 8-12 years. There were notable differences between the 44 who developed prostate cancer and the rest who didn’t:

“”Men with prostate cancer diagnosis had a higher systolic and diastolic blood pressure, were more obese as measured by BMI, waist and hip measurements than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level, and a higher fasting serum insulin level than men who did not have prostate cancer diagnosis at follow-up.”

All of these accessory factors—blood pressure, BMI, waist and hip circumference, uric acid—are directly related to elevated insulin. Considering the prevalence of both prostate cancer and metabolic syndrome (high insulin), it’s important for clinicians and the public alike to bear in mind the authors’ conclusion:

“Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.“

Alcohol

“…cellular and biochemical mechanisms of alcohol-induced oxidative damage in different types of brain cells.”

Interestingly, alcohol administration generated increased levels of reactive oxygen species (‘free radicals’) localized mainly in the astrocytes and microglia (‘housekeeper’ immune cells in the brain). As a result,

“Oxidative damage in glial cells was accompanied by their pronounced activation (astrogliosis) and coincident neuronal loss, suggesting that inflammation in glial cells caused neuronal degeneration.“

In other words, the oxidative stress induced by alcohol resulted in an autoimmune inflammatory attack on brain tissue. But here’s the good news:

“Co-administration of ALC [acetyl-L-carnitine] with alcohol showed a significant reduction in oxidative damage, neuronal loss and a restoration of synaptic neurotransmission in this brain region, suggesting that ALC protects brain cells from ethanol-induced oxidative injury. These findings suggest the potential clinical utility of ALC as a neuroprotective agent that prevents alcohol-induced brain damage and development of neurological disorders.”

“Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex…”

This is an amazing demonstration. In order to protect the brain from a stroke caused by permanent blockage of a major artery there has to be a rapid reperfusion of the area deprived of blood and oxygen. The authors proved with blood flow imaging and other techniques that by stroking a single whisker (if done soon enough,…

“Animals that receive early treatment are histologically [cellular anatomy] and behaviorally equivalent to healthy controls and have normal neuronal function.”

Stroking induced sufficient opening of collateral vessels to provide an alternative arterial source, enough for reperfusion even though the middle cerebral artery was still blocked. The authors’ conclusion is a fascinating insight into the therapeutic potential of sensory based peripheral stimulation therapies (chiropractic, acupuncture, massage, etc.) to elicit profound improvements in autonomic regulatory function:

“These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential.”

This research is consonant with my clinical experience in using sensory based peripheral therapies as a regulating stimulus for both acute and chronic conditions.

“The aim of this study was to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans…Endothelial dysfunction has been identified as an independent predictor of cardiovascular events.”

Study subjects were assigned to either gain weight or maintain the same weight while a number of functional indicators were tracked along with body composition. The metric for endothelial function was brachial artery flow-mediated dilation [FMD]. The weight gainers then lost the added weight for the final measurements. What did the data show? First the bad news, then the good:

“FMD decreased in fat gainers but recovered to baseline when subjects shed the gained weight.“

Subcutaneous fat gain did not degrade endothelial function. The authors sum up their findings by concluding:

“In normal-weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction.”

So ‘it’s not over until the fat lady loses the weight around her waist.’

“Attention-deficit/hyperactivity disorder is a neurobiological syndrome with an estimated prevalence among children and adolescents of 5%. It is a highly heritable disorder, but acquired factors in etiology are sometimes uncovered that may be amenable to preventive measures or specific therapy.“

The others go on to suggest an organic theory and genetic and biochemical basis for attention-deficit/hyperactivity disorder along with an etiologic (causal) classification, taking into consideration environmental, prenatal, perinatal and postnatal factors including illnesses, injuries and deficiencies.

A series of studies published in Biological Psychiatry offer insight into how attentional and behavioral disorders are linked to variations in the very structure of the brain and its component anatomy. The authors of Structural Brain Imaging of Attention-Deficit/Hyperactivity Disorder observe:

“Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum…The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized.”

These authors refer to, among others, an earlier study published under the title Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder.

“Boys with ADHD had (on average) 8.3% smaller total cerebral volumes…Findings suggest that ADHD is associated with decreased frontal lobe gray and white matter volumes. More than one subdivision of the frontal lobes appears to be reduced in volume, suggesting that the clinical picture of ADHD encompasses dysfunctions attributable to anomalous development of both premotor and prefrontal cortices.“

Later in the same journal Temporal Lobe Dysfunction in Medication-Naïve Boys With Attention-Deficit/Hyperactivity Disorder During Attention Allocation and Its Relation to Response Variability established that abnormalities could be documented in the temporal lobes as well:

“Patients showed significantly reduced brain activation in left and right superior temporal lobes, basal ganglia, and posterior cingulate…Brain abnormalities in patients with ADHD are not confined to fronto-striatal networks mediating executive functions but are also observed in temporo-striatal and cingulate regions…”

Biological Psychiatry was also the venue for documenting abnormalities in the corpus callosum (the structure connecting the right and left brain hemispheres) in Decreased Callosal Thickness in Attention-Deficit/Hyperactivity Disorder. The authors observe:

“Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have revealed structural abnormalities in the brains of affected individuals. One of the most replicated alterations is a significantly smaller corpus callosum (CC)…”

They used advanced imaging techniques to refine and further validate these observations:

“In close agreement with many prior observations, the CC was shown to be significantly thinner in ADHD subjects…Decreased callosal thickness may be associated with fewer fibers or a decrease in the myelination of fibers connecting the parietal and prefrontal cortices. This might affect interhemispheric communication channels that are necessary to sustain attention or motor control, thus contributing to symptoms of hyperactivity and impulsivity, or inattention, observed in ADHD.“

Recently the same journal presented evidence of abnormalities in another brain region in the paper Ventro-Striatal Reductions Underpin Symptoms of Hyperactivity and Impulsivity in Attention-Deficit/Hyperactivity Disorder. This research is significant for its investigation of the reward centers in the brain. The authors observe:

“The neural bases of reward processes have barely been explored in relation to this disorder, in contrast to extensive neuroimaging studies that examine executive functions in patients with ADHD.”

The authors examined volumetric differences in the ventral striatum of ADHD children and found substantial correlations:

“The ADHD children presented significant reductions in both right and left ventro-striatal volumes. In addition, we found that the volume of the right ventral striatum negatively correlated with maternal ratings of hyperactivity/impulsivity…Our study provides neuroanatomical evidence of alterations in the ventral striatum of ADHD children…the negative correlations we observed strongly uphold the relation between the ventral striatum and symptoms of hyperactivity/impulsivity.“

A paper published in the French medical journal L’Encéphale, sums up the ever-growing scientific literature in this field. Under the title Structural and functional neuroanatomy of attention-deficit hyperactivity disorder (ADHD), the authors observe:

“Three subtypes of the disorder have been proposed in the current clinical view of ADHD: inattentive, hyperactive-impulsive and combined type. Numerous problems are associated with ADHD: poor academic performance, learning disorders, subtle cognitive deficits, conduct disorders, antisocial personality disorder, poor social relationships, and a higher incidence of anxiety and depression symptoms into adulthood. ..From the neuropsychological viewpoint, impairment of the “hot” affective aspects of executive functions, like behavioural inhibition and attention and the more cognitive, “cool” aspects of executive functions like self-regulation, working memory, planning, and cognitive flexibility, are often reported by studies on ADHD. The hot executive functions are associated with ventral and medial regions of the prefrontal cortex (including the anterior cingulated cortex) and named “hotbrain” and the cool executive functions are associated with the dorsolateral prefrontal cortex and are called “coolbrain”.

The potential anatomical areas of interest are extensive:

“Convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD…Moreover, a growing literature demonstrates abnormalities affecting other cortical regions and the cerebellum…Anatomical studies suggest widespread reductions in volume throughout the cerebrum and cerebellum, while functional imaging studies suggest that affected individuals activate more diffuse areas than controls during the performance of cognitive tasks…Furthermore, hypoactivation of the dorsal anterior cingulate cortex, the frontal cortex and the basal ganglia (striatum) have also been reported.”

As always, biological individuality rules—every child is different. Subsequent posts offer insights into the various underlying causes of these abnormalities in brain anatomy, how to test for them, and what to do about them.

“Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect.”

They analyzed plasma resveratrol and FMD after varying doses of resveratrol in overweight and mildly hypertensive study subjects in a double-blind, randomized crossover comparison. What did the data show?

“There was a significant dose effect of resveratrol on plasma resveratrol concentration and on FMD, which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log10 plasma resveratrol concentration.”

This means that resveratrol caused a significant improvement in the ability of the blood vessels to dilate (open) that corresponded closely to the dose. The cardiovascular benefits are obvious, but we can thank the research reported in the previous post for documenting the profound benefits for brain health that result from improving the capacity for the blood to get through to the tissues.

The authors conclude:

“Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner.”

“Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury.“

They set out to test whether the cardiac index (the amount of blood the heart pumps in proportion to body size) as a metric for cardiac function would correlate with loss of brain tissue as shown by brain MRI and neuropsychological markers of ischemia (reduction of oxygen due reduced blood flow) and Alzheimer’s disease. What did the data show?

“…cardiac index was positively related to total brain volume and information processing speed and inversely related to lateral ventricular volume…participants in the bottom cardiac index tertile and middle cardiac index tertile had significantly lower brain volumes than participants in the top cardiac index tertile.”

Even the people with the middle cardiac group (low normal) had showed signs of serious neurodegeneration with brain atrophy (lower brain volume). How important is it to get better than a low normal amount of blood to the brain?

“Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.“

Consider this in light of earlier research that aggressive treatment of blood pressure is harmful. Clinicians must respect the need to balance cardiovascular protection from excessive pressure dynamics with the profound need to ensure adequate cerebral perfusion. Are you concerned that your blood pressure therapy may be stronger than it should? Read the earlier research posts and discuss the matter with your doctor.

“Ataxia is the commonest neurological manifestation of coeliac disease. Some individuals with genetic susceptibility to the disease have serological evidence of gluten sensitivity without overt gastrointestinal symptoms or evidence of small-bowel inflammation. The sole manifestation of disease in such patients may be ataxia.”

The authors carried out clinical, neurophysiological, neuroradiological, and neuropathological examinations patients with antibodies to gliadin (the immunoreactive component of gluten):

“28 patients with gluten ataxia were identified. All had gait ataxia and most had limb ataxia….16 patients had no gastrointestinal symptoms…Six patients had evidence of cerebellar atrophy on magnetic-resonance imaging. Necropsy was done on two patients who died; there was lymphocytic infiltration of the cerebellum, damage to the posterior columns of the spinal cord, and sparse infiltration of the peripheral nerves.”

A key point is that most of the patients whose gluten sensitivity caused severe neurological damage had no gastrointestinal symptoms.

The authors conclude:

“Gluten sensitivity is an important cause of apparently idiopathic ataxia and may be progressive. The ataxia is a result of immunological damage to the cerebellum, to the posterior columns of the spinal cord, and to peripheral nerves.“