Archive for the ‘Brain Health’ Category

Neurological disease with GAD antibodies and gluten sensitivity

Thursday, September 2nd, 2010

GAD (glutamic acid decarboxylase) antibodies are expressed in type 1 (autoimmune) diabetes, adrenal failure (Addison disease), autoimmune thyroid diseases, premature ovarian failure, myasthenia gravis, pernicious anemia, Stiff-man syndrome and a number of other disorders. An informative study recently published in Acta Neurologica Scandinavica documents the link between these conditions and gluten sensitivity. The authors state:

“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.

Acetyl-L-carnitine protects the brain from alcohol-induced damage

Tuesday, August 31st, 2010

Alcohol in excess is a significant promoter of accelerated neurodegeneration. The authors of a welcome paper recently published in Free Radical Biology and Medicine first elucidate the…

“…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.”

Disorders of learning and behavior are linked to brain abnormalities

Saturday, August 28th, 2010

Rapidly developing science in this field is bringing to light more understanding of the biological basis of learning and behavioral disorders. A paper published not long ago in the journal Pediatrics introduces a classification of attention-deficit/hyperactivity disorder according to underlying organic causes. The authors first observe:

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.

Resveratrol helps get blood to the tissues (including brain)

Friday, August 27th, 2010

The previous post documented that suboptimal blood perfusion results in brain shrinkage. The endothelium (inner lining of blood vessels) regulates local vascular dilation (opening) and constriction. Welcome research just published in the journal Nutrition, Metabolism and Cardiovascular Diseases offers evidence that resveratrol improves endothelial function even in obese subjects. The authors state:

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.”

Brain health is linked to heart health, implications for blood pressure medication

Thursday, August 26th, 2010

An interesting study just published in the journal Circulation provides evidence of the link between brain health and the capacity of the heart to send blood to the brain. The authors first note the importance of cerebral perfusion (getting blood into the brain):

“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.

Feeling uncoordinated? Gluten sensitivity and ataxia

Wednesday, August 25th, 2010

A paper published a while back in the prestigious medical journal The Lancet is a useful reminder of a common neurological disorder resulting from gluten sensitivity that manifests as problems with coordination and balance. The authors state:

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.

Inflammation, mitochondrial dysfunction and neurodegeneration in major depression

Saturday, August 21st, 2010

Is depression mainly a disorder of serotonin regulation? A paper just published in Progress in Neuro-Psychopharmacology and Biological Psychiatry reminds us that, of course, it is not. The authors state:

“For many years, a deficiency of monoamines including serotonin has been the prevailing hypothesis on depression, yet research has failed to confirm consistent relations between brain serotonin and depression.

They observe that there is a relationship between depression a number of other conditions with a common set of underlying causes:

“…depression is one of a family of related conditions sometimes referred to as the “affective spectrum disorders”, and variably including migraine, irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia and generalized anxiety disorder, among many others.”

What do these disorders have in common?

“…we present data from many different experimental modalities that strongly suggest components of mitochondrial dysfunction and inflammation in the pathogenesis of depression and other affective spectrum disorders. The three concepts of monoamines, energy metabolism and inflammatory pathways are inter-related in many complex manners. For example, the major categories of drugs used to treat depression have been demonstrated to exert effects on mitochondria and inflammation, as well as on monoamines. Furthermore, commonly-used mitochondrial-targeted treatments exert effects on mitochondria and inflammation, and are increasingly being shown to demonstrate efficacy in the affective spectrum disorders.”

In the functional approach, the evaluation and treatment of depression is not complete without addressing the factors that contribute to neuroinflammation, neurodegeneration and mitochondrial dysfunction with the appropriate tests and physiological interventions.

Irritable bowel syndrome—a brain disorder

Tuesday, August 17th, 2010

Irritable bowel syndrome (IBS) can manifest with abdominal pain and diarrhea, or constipation, or both. A study just published in the journal Gastroenterology brings to light the role of the brain in IBS. The authors first observe:

“Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous.”

They used MRI methods to examine anatomical differences in the brains of carefully screened IBS patients and normal ‘controls’. Interestingly, they found significant abnormalities in the brains of the IBS group:

IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain [gray matter refers to the neuronal cell bodies]…The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms.”

The brain regions most affected included the prefrontal and posterior parietal cortices, leading to their conclusion:

Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS…”

Evaluation and treatment of irritable bowel syndrome, like so many other diverse conditions, must include the capacity of the brain to regulate its arousal state in general and the autonomic nervous system (which governs digestive and all other visceral functions) in particular.

Menstrual pain changes the brain, meditation helps

Saturday, August 14th, 2010

The authors of a paper just published in the journal Pain report that pain from primary dysmenorrhea (PDM) can produce structural changes in the brain that make the subsequent experience of pain worse. The authors note:

“Prolonged nociceptive [painful] input to the central nervous system can induce functional and structural alterations throughout the nervous system. In PDM, a chronic viscero-nociceptive drive of cyclic nature, indications of central sensitization and altered brain metabolism suggest a substantial central reorganization.”

The authors tested their earlier hypothesis that loss of inhibition [calming] of orbitofrontal networks [neural circuits in the frontal areas in the region of the eyes] could result in increased pain and negative feelings with menstrual pain. They used a type of brain MRI called voxel-based morphometry to measure differences in the amount of  gray matter (GM) in subjects with and without PDM. What did their data show?

Abnormal decreases were found in regions involved in pain transmission, higher level sensory processing, and affected regulation while increases were found in regions involved in pain modulation and in regulation of endocrine function. Moreover, GM changes in regions involved in top-down pain modulation and in generation of negative affect were related to the severity of the experienced PDM pain.”

The most striking and important finding was articulated in their conclusion:

“Our results demonstrate that abnormal GM volume changes are present in PDM patients even in the absence of pain. These changes may underpin a combination of impaired pain inhibition, increased pain facilitation and increased affect. Our findings highlight that longer lasting central changes may occur not only in sustained chronic pain conditions but also in cyclic occurring pain conditions.”

Interestingly, another paper in the same issue of the same journal offers EEG evidence that meditation reduces the negative experience of pain.

“In this study we compared a group of individuals with meditation experience to a control group to test whether any differences in the affective appraisal of pain could be explained by lower anticipatory neural processing.”

The authors used anticipatory and pain-evoked ERP (event related potentials measured by electroencephalography) data and pain unpleasantness reported by test subjects to determine whether experience with meditation made a difference. What did the data show?

“More experienced meditators perceived the pain as less unpleasant relative to controls, with meditation experience correlating inversely with unpleasantness ratings. ERP source data for anticipation showed that in meditators, lower activity in midcingulate cortex relative to controls was related to the lower unpleasantness ratings, and was predicted by lifetime meditation experience.”

Meditators also had less medial prefrontal cortical activity engaged in anticipating pain unpleasantness. The authors concluded:

“Our data is consistent with the hypothesis that meditation reduces the anticipation and negative appraisal of pain…”

Bulimia and brain inflammation

Thursday, August 5th, 2010

Bulimia nervosa is another example of a behavioral condition that for thorough assessment, treatment and optimal outcomes should be examined for its neuroinflammatory component. Consider this paper published in the journal Clinical Endocrinology that identifies the brain as the source of the inflammatory cytokine TNF-α (tumor necrosis factor alpha) in individuals suffering with bulimia.

Tumor necrosis factor-α (TNF-α) is a cytokine with numerous immunological and metabolic activities. In addition, TNF-α can stimulate a variety of physiological, neuroendocrine and behavioural responses of the central nervous system. In experimental animals, TNF-α induces changes in physiological and behavioural parameters which have also been observed in eating disorders.”

They measured plasma concentrations of TNF-α and its receptors, TNF-RI and TNF-RII (which are shed in increased amounts when TNF-α is released) in bulimic individuals compared to normal controls. What did the data show?

“Plasma TNF-α concentrations in BN [bulimia nervosa] were significantly higher than those in N [the normal group]…plasma sTNF-RII concentrations in BN were significantly higher than those in N.”

Hence their conclusion:

“Our present findings suggest that the adipose tissue may not be the immediate source of TNF-α in bulimic patients but the increase in plasma TNF-α in these patients may be derived from the central nervous system sources.”

That means increased brain microglial inflammatory activity. The practical message is that bulimia nervosa should be evaluated with the appropriate objective tests to resolve the brain inflammation component, the foundation of the biological component of treatment for this disorder.