Brain health is maintained by immune system activity

the-scientistDramatic advances in understanding how brain health is maintained by the immune system are described in an excellent article published recently in The Scientist that accompanies the brief video presentation by neuroscientist Michal Schwartz shown below. Only recently has it been recognized that brain immune function is integrated with the systemic immune system.

Until recently, the brain and the spinal cord were considered immune-privileged sites, strictly cordoned off from immune cells unless something went terribly wrong. Researchers knew, for example, that multiple sclerosis (MS) was caused by T cells that breach the selective border called the blood-brain barrier (BBB), enter the CNS, and attack the myelin sheath covering neurons. Even microglia, specialized macrophage-like immune cells that scientists had recognized as normal CNS residents since the 1960s, were mainly studied in the context of disease.”

Now the pervasive role of the immune system in brain function and maintenance is being observed:

“But over the past two decades, researchers have recognized that the entire immune system is very much a part of a functional CNS, with vital roles in cognition, injury repair, neurodegenerative disease, and sensory systems. Microglia pervade the CNS, including the white and gray matter that constitute the organ’s parenchyma. Other immune cells, including T cells, monocytes, and mast cells, reside in the brain and spinal cord’s outer membranes, known as the meninges, and circulate in cerebrospinal fluid (CSF).”

Immune cells in the brain help repair damage

It was formerly thought that immune cell activity in the brain was only harmful.

Macrophages, for example, can damage neurons by secreting cytokines, proteases, or reactive oxygen species, but in rat and mouse models of spinal cord injury, they also produce transforming growth factor-beta (TGFβ), which promotes wound healing,5 and interleukin 10 (IL-10) which helps resolve inflammation. By the late 2000s, researchers recognized that different subtypes of macrophages can benefit neuronal growth in rodents, and that some were critical to recovery. Views also began to change on the clinical side after the 2004 Corticosteroid Randomization After Significant Head Injury (CRASH) study showed that corticosteroids didn’t help brain injury patients recover, but increased their risk of disability and death.”

Cells of the adaptive immune system residing in the tissue lining of the ventricles can also assist in repair.

Her team also showed that T cells present in this lining, called thechoroid plexus, secrete cytokines such as interferon gamma (IFNγ), which allows selective passage of CD4+ T cells and monocytes from the blood into CSF within the ventricles.  In a model of spinal cord bruising, mice deficient for the IFNγ receptor had reduced immune cell trafficking across the choroid plexus and poor recovery of limb movement. And last year, Kipnis’s team reported that IL-4 produced by CD4+ T cells in the CNS signals neurons to regrow axons after spinal cord or optic nerve injury.”

Immune cells in the brainAn intact blood-brain barrier (BBB), however, is essential:

“His team also found that microglia reinforce the BBB, which is composed of endothelial cells, pericytes, and astrocytes. Microglia fill in spaces left by astrocytes killed or damaged during injury. Without a robust barrier, McGavern says, unwanted immune cells may flood the parenchyma and do more harm than good.”

Immune cells residing in the CSF and choroid plexus

Immune cells residing in the CSF and choroid plexus

Brain needs both anti-inflammatory and pro-inflammatory activity for cognition

Neuroinflammation is well known to be a core feature of neurodegenerative disorders, but inflammatory immune activity is also required for healthy cognition.

“…Rivest used two-photon microscopy to monitor monocytes in blood vessels of living mouse brains, and he watched as the cells migrated toward and cleared amyloid-β deposits within veins. When the researchers selectively depleted monocytes, the mice developed more amyloid-β plaques in the cortex and hippocampus. And when they knocked out the innate immune signaling protein MyD88, which mediates signals from several monocyte-activating receptors, the mice also experienced more amyloid-β accumulation, accompanied by accelerated cognitive decline.”

Even in the classic disease of neuroinflammation, MS, immune cell activity is necessary:

“Rivest’s team found that microglia-forming monocytes are beneficial in a model of MS, where microglia are found within the inflammatory lesions. Last year, the researchers reported that inhibiting monocytes from entering the CNS reduced the clearance of damaged myelin and impeded proper remyelination.”

Evidence for the immune system’s role in preventing neurodegeneration continues to mount:

“Schwartz has similarly found evidence for the immune system’s ability to protect against neurodegeneration. Last year, she and her colleagues reported that the choroid plexus epithelium was less permissive to immune cell trafficking in a mouse model of Alzheimer’s disease than in wild-type mice, due to anti-inflammatory signals produced by regulatory T cells (Tregs). They found that depleting Tregs in Alzheimer’s mice allowed macrophages and CD4+ T cells into the brain, reduced the number of amyloid-β plaques, and improved cognition. Similarly, blocking the T-cell checkpoint protein PD1, which normally supports Treg survival while suppressing the activity of other T cells, reduced amyloid-β plaques in mouse brains and improved the animals’ scores in a learning and memory water maze test.”

Clinicians should be alert to evaluate and support balance

Too much neuroinflammation is clearly adverse.

“But there’s a reason that scientists have believed that immune activity contributes to Alzheimer’s damage: microglia, perhaps best known for trimming back synapses, have the potential to become overzealous, and excessive synapse pruning can cause neural damage in a variety of CNS diseases. By blocking the cells’ proliferation in mice, Diego Gomez-Nicola of the University of Southampton in the U.K. has successfully alleviated symptoms of Alzheimer’s disease, amyotrophic lateral sclerosis, and prion disease. And earlier this year, Beth Stevens of the Broad Institute and her colleagues reported that inhibiting a protein that tags synapses for microglial pruning halted over-pruning and loss of synapse signaling strength in two mouse models of Alzheimer’s disease.”

Regulation of stress is critical

Stress has a major effect on which way the ‘two-edged sword’ swings.

“Kipnis says regulation of stress may be linked to T cells’ role in learning. Stress can signal macrophages to secrete proinflammatory cytokines, some of which block a protein called brain-derived neurotrophic factor (BDNF), which astrocytes need to support learning and memory. CD4+ T cells in the meninges make more IL-4 cytokine after mice have been trained in a water maze—a stressful exercise for the animals—suggesting the signaling molecule might let macrophages know when the brain is dealing with the stress of learning something new, not the stress of an infection. “They tell macrophages, ‘Don’t overshoot,’” says Kipnis. In mice whose meninges are depleted of CD4+ T cells and thus deficient for IL-4, macrophages secrete proinflammatory factors unchecked in times of stress, disrupting their ability to learn and form memories.”

But excess suppression of inflammatory activity in the brain could have unwanted consequences as in the case of mast cells:

“Best known for their involvement in allergic responses in the upper airway, skin, and gastrointestinal tract, mast cells have been found in the meninges as well as in perivascular spaces of the thalamus, hypothalamus, and amygdala. They are known to quickly recruit large numbers of other immune cell types to sites of inflammation, and to play a role in MS. But mast cells also release serotonin into the hippocampus, where the molecule aids neurogenesis, supports learning and memory, and regulates anxiety.”

A ‘goldilocks zone’ for immune activity in the brain

As in every condition clinical evaluation must embrace the whole context…

“Thus, like microglia, mast cells are a double-edged sword when it comes to neural health. It’s a reflection of the entire immune system’s love-hate relationship with the CNS, Kipnis says. “Saying the immune system is always good for the brain, it’s wrong; saying it’s always bad for the brain, it’s wrong. It depends on the conditions.”

Neuroscientist Michal Schwartz — Breaking The Wall Between Body and Mind

 

Alzheimer’s disease and blood-brain barrier leakage

RadiologyAlzheimer’s disease is not a unitary condition but variable in causation at the individual level like all complex chronic disorders. Neuroinflammation, metabolic damage, vascular compromise, accumulation of noxious debris (amyloid β and tau), impairments in brain CSF and lymphatic drainage and other causes can all variously contribute to Alzheimer’s and other dementias. Now original research recently published in the journal Radiology demonstrates that leakiness of the blood-brain barrier (BBB) can permit an environment hostile to neuronal health that contributes to cognitive decline, Alzheimer’s and other dementias. The authors state:

“Evidence is increasing that impairment of the cerebral microvasculature is a contributing factor in the pathophysiology of Alzheimer disease (AD). However, the exact pathway remains unclear. Results of histologic evaluation and albumin sampling studies show that an increased permeability of the blood-brain barrier (BBB) is likely a key mechanism.”

An intact blood-brain barrier is essential for brain health

The BBB is a collection of cells and other structures in the cerebrovascular wall that when healthy permits only privileged access into the brain from the extra-cerebral blood compartment.

“It regulates the delivery of important nutrients to the brain through active and passive transport mechanisms and prevents neurotoxins from entering the brain. It also has a clearance function, meaning that it removes surplus substances from the brain. A well-functioning BBB is essential to keeping the brain tissue in a healthy condition. Results of previous studies suggest that deterioration of the BBB can cause an ill-conditioned environment for neuronal cells and other pathologic changes such as small-vessel abnormality, protein deposits, inflammation, and neuronal cell death. These changes eventually may lead to cognitive decline and dementia.”

Early Alzheimer’s shows abnormal BBB permeability

Blood-brain barrier degradation has earlier been demonstrated in advanced Alzheimer’s disease. Here the authors examined whether or not BBB leakage contributes to the early stages of disease.

“To investigate whether BBB leakage contributes to the early pathophysiology of AD, we hypothesized that patients with early forms of AD already show increased BBB permeability in comparison with age-matched control subjects. For this pilot study, we used a dedicated dynamic contrast-enhanced MR imaging acquisition protocol with dual-time resolution that separates the filling of the blood vessels from the leakage. We also investigated differences in local blood plasma volume fraction, and the relationship between BBB permeability and global cognition.”

The analyzed data for patients diagnosed with mild cognitive impairment (MCI) due to AD or patients or patients with early AD (a continuum of cognitive decline who had been referred by general practitioners because of memory concerns, in comparison with healthy controls. Individuals with dementia of vascular origin were excluded, as were those with major cardiovascular and neuropsychiatric disorders, Parkinson’s, MS, trauma, major structural abnormalities of the brain, and alcohol or drug abuse. They indeed demonstrated a marked distinction between their study subjects and controls:

“The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total GM (grey matter) and cortex but not in the WM, normal-appearing WM, deep GM, or WM hyperintensities…When adjustments were made for all covariates, the patients exhibited a significantly higher leakage volume in the WM and GM and also in the normal-appearing WM, deep GM, cortex, but not in WM hyperintensities…The median blood plasma volume was significantly lower in the patients than in the control subjects in all tissue classes.”

BBB leakage rate shown in early Alzheimer's

BBB leakage rate shown on the right, with some periventricular hot spots

BBB leakage in early Alzheimer’s is widespread

The leakage is not due to vascular abnormalities, and leakage volume was even more striking than rate:

The results of this study showed increased BBB leakage in patients with early AD. The leakage was globally distributed throughout the cerebrum and was associated with declined global cognitive performance. By using dynamic contrast-enhanced MR imaging with dual-time resolution, we found an increased BBB leakage rate in the GM of patients with early AD. By also showing very subtle BBB impairment in the WM, leakage volume proved to be even more sensitive to the differences in BBB leakage than was the leakage rate. Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class such as WM hyperintensities, normal-appearing WM, or cortex. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.”

Breakdown in tight junctions like the intestinal barrier

The intestinal barrier, critical for healthy immune system regulation, loses integrity with a breakdown of the tight cellular junctions. So too with the blood-brain barrier.

“The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis.”

Toxic accumulations in the brain and cognitive impairment

The authors have demonstrated that BBB leakage tracks cognitive impairment in early Alzheimer’s:

“We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.”

BBB and amyloid β

Clearance of amyloid β is also impaired:

“…amyloid β is actively transported across the BBB, whereas gadolinium leaks passively through the tight junctions. Previous work with positron emission tomographic data has shown that clearance of amyloid β is also impaired in patients with AD. An impaired clearance of amyloid β would mean that the BBB is impaired in different ways, contributing to the pathologic cascade leading to AD.”

Most importantly…

“Therefore, BBB leakage may help to provide a biomarker for early diagnosis, or at least a marker indicating vulnerability for the development of dementia. Successful prediction of dementia eventually might lead to optimized treatment, delay, or even prevention of the disease.”

Clinical note

Early diagnosis is key here, and for those of us without dynamic gadolinium contrast-enhanced MR imaging at hand I highly recommend the Blood Brain Barrier Permeability™ screen from Cyrex Labs (Array 20) which offers the clinician the ability to detect early changes in BBB permeability. Clinicians experienced in rehabilitation of the gut barrier will be familiar with resources to evaluate and remediate inflammation and other insults to the blood-brain barrier.

The authors conclude:

“…in this pilot study, MR imaging was used to show global, diffusely distributed BBB leakage in patients with early AD, which suggests that a compromised BBB is part of the early pathology of AD and might be part of a cascade of pathologic events that eventually lead to cognitive decline.”

  • “Patients with early Alzheimer disease have significantly more tissue characterized by blood-brain barrier leakage than do healthy control subjects, both in the normal-appearing white matter and in the gray matter.
  • Blood-brain barrier leakage in the gray matter correlates with lower scores on the Mini-Mental State Examination.”

Insulin in the brain affects cognition, appetite and weight

Nature Reviews EndocrinologyInsulin has long been known as crucial for muscle, liver and adipose tissue metabolism. It’s effect in the brain on cognition, behavior and physiology is a more recent focus described in an excellent paper published recently in Nature Reviews Endocrinology.

The brain is sensitive to insulin

Since glucose uptake into the brain occurs independently it took a while to recognize the function of the receptors that are found there. The first clue came with the brain-specific knockout mouse model of the insulin receptor.

“Such knockout mice became obese due to increased food intake and developed whole-body insulin resistance with increased plasma levels of insulin and dyslipidaemia.”

Insulin-sensitive brain areasThen investigations comparing infusion of insulin versus saline on human brain activity has widespread effects.

“…these studies provided strong evidence that systemic insulin administration modulates cortical brain activity in humans…not only homeostatic areas (as shown in animal studies) but also higher functional areas involved in sensory and cognitive processes.”

And intranasal administration was shown to affect basal and evoked brain activity. How does it naturally get there?

Whole body insulin resistance affects the brain

“…various studies in animals clearly demonstrated that insulin was transported across the blood–brain barrier by a saturable transport system…”

And it humans it gets from the CSF (cerebrospinal fluid) through the BBB (blood brain barrier).

“Concentrations of insulin in the CSF increase when the hormone is administered into the bloodstream, again indicating transport across the blood–CSF barrier.”

Importantly, insulin resistance in the rest of the body affects the brain, and this has been associated with Alzheimer’s disease.

Insulin transport into CSF is attenuated in individuals with reduced whole-body insulin sensitivity, which suggests that insulin resistance at the blood–CSF barrier could impair transport of the hormone into the brain. Accordingly, insulin concentrations in CSF are lower in individuals with obesity, who are generally more insulin resistant, than in people without obesity. Furthermore, insulin concentrations within brain tissue and CSF are reduced in older individuals…In Alzheimer disease, a condition often associated with insulin resistance, insulin levels in the CSF have been reported to be reduced.”

 

Side sleeping helps clean brain through glymphatic transport

Journal of NeuroscienceSleep is a physiological imperative because metabolic waste and other harmful substances, including  amyloid beta, are flushed from the brain as the neurons contract to allow enhanced drainage through the glymphatic system (as described in Stunning discovery links brain and immune system). Now scientists who published the groundbreaking study entitled Sleep Drives Metabolite Clearance from the Adult Brain have reported their investigation into the effect of sleep posture on brain clearance of wastes in a paper published in The Journal of Neuroscience. The authors state:

“The glymphatic pathway expedites clearance of waste, including soluble amyloid beta (Aβ) from the brain. Transport through this pathway is controlled by the brain‘s arousal level because, during sleep or anesthesia, the brain‘s interstitial space volume expands (compared with wakefulness), resulting in faster waste removal. Humans, as well as animals, exhibit different body postures during sleep, which may also affect waste removal. Therefore, not only the level of consciousness, but also body posture, might affect CSF-interstitial fluid (ISF) exchange efficiency.”

They quantified CSF (cerebrospinal fluid) and ISF exchange rates with dynamic-contrast-enhanced MRI in their subjects’ brains in supine, prone and lateral lying postures, adding fluorescence microscopy and radioactive tracers to measure clearance of Aβ. The lateral (side-lying) posture was clearly the best for ‘flushing’ the brain:

“The analysis showed that glymphatic transport was most efficient in the lateral position compared with the supine or prone positions. In the prone position…transport was characterized by “retention” of the tracer, slower clearance, and more CSF efflux along larger caliber cervical vessels.”

Glymphatic transport during sleep clears brain Aβ

The brain ‘takes out the trash’ during sleep, and the lateral/side-lying posture appears to be superior in facilitating brain ‘drainage’.

“The major finding of our study was that waste, including Aβ, removal was most efficient in the lateral position…We propose that the most popular sleep posture (lateral) has evolved to optimize waste removal during sleep and that posture must be considered in diagnostic imaging procedures developed in the future to assess CSF-ISF transport in humans.”

Clinical Note

The rhythmic expansion and contraction of the cranium associated with CSF hydraulics helps drive transport through the glymphatic system. This highlights the clinical value of treatment methods that relieve restrictions in cranial motion such as BioCranial Therapy.

Stunning discovery links brain and immune system

NatureLong established scientific dogma asserts that there is no direct connection by vessels between the brain and immune system, yet the link between systemic inflammation, brain inflammation and neurodegeneration is vividly evident in clinical practice (see Systemic inflammation drives brain neurodegeneration and numerous related posts). Now investigators report in the prestigious journal Nature the stunning discovery of a central nervous system lymphatic system connecting the brain and immune system in a paper entitled Structural and functional features of central nervous system lymphatic vessels.

“One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.”

Changes the landscape of neuroimmunology

Brain inflammation, a key factor in neuropsychiatric and neurodegenerative disorders, is linked directly to systems-wide immune function.

The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.”

Neuroinflammation’s mechanism re-defined

Neuroscience NewsAutism and bipolar disorder, Alzheimer’s and MS, and every other neuroinflammatory brain based disorder must be considered in this light. A commentary entitled Researchers Find Missing Link Between the Brain and Immune System in Neuroscience News states:

“That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer’s disease to multiple sclerosis.”

Quoting lead author Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG):

“Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels…It changes entirely the way we perceive the neuro-immune interaction…We believe that for every neurological disease that has an immune component to it, these vessels may play a major role.

Metabolic purpose of sleep

ScienceThe discovery of lymphatic vessels providing brain drainage reminds of the remarkable research entitled Sleep Drives Metabolic Clearance from the Adult Brain, published in the competing journal Science, that brilliantly demonstrates the metabolic purpose of sleep. The authors state:

“The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.”

In other words, they demonstrated that brain cells shrink during sleep to increase the interstitial space by a whopping 60%, and further showed that this results in marked increase drainage of toxic metabolites through the ‘glymphatic‘ system. This paper was published before the stunning discovery of the brain’s own lymphatic system.

Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ), α-synuclein, and tau, are present in the interstitial space surrounding cells of the brain. In peripheral tissue, lymph vessels return excess interstitial proteins to the general circulation for degradation in the liver. Yet despite its high metabolic rate and the fragility of neurons to toxic waste products, the brain lacks a conventional lymphatic system. Instead, cerebrospinal fluid (CSF) recirculates through the brain, interchanging with interstitial fluid (ISF) and removing interstitial proteins, including Aβ. The convective exchange of CSF and ISF is organized around the cerebral vasculature, with CSF influx around arteries, whereas ISF exits along veins. These pathways were named the glymphatic system on the basis of their dependence on astrocytic aquaporin-4 (AQP4) water channels and the adoption of functions homologous to peripheral lymphatic removal of interstitial metabolic byproducts. Deletion of AQP4 channels reduces clearance of exogenous Aβ by 65%, suggesting that convective movement of ISF is a substantial contributor to the removal of interstitial waste products and other products of cellular activity. The interstitial concentration of Aβ is higher in awake than in sleeping rodents and humans, possibly indicating that wakefulness is associated with increased Aβ production. We tested the alternative hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates glymphatic clearance.”

The convective movement of brain interstitial fluid that they describe is only enhanced by lymphatic vessels that drain the brain. Sleep is the time when the brain ‘takes out the trash’.

Tremendous clinical significance

Cranial therapy that restores the amplitude and symmetry of the rhythmic expansion and contraction the skull associated with the circulation of cerebrospinal spinal fluid (CSF) and lymphatic exchange in the brain can be appreciated in this context along with the immunological implications. Further commenting in Neuroscience News:

“The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.”

Maps of the lymphatic system

Insulin resistance damages brain white matter even with normal glucose

Neurology 82 (18)Insulin resistance (IR) exposes the brain along with the rest of the body to elevated insulin levels produced to overcome receptor resistance. Following earlier studies noted here including Dementia risk increased by higher blood sugar before diabetes, a new study just published in the journal Neurology offers yet more evidence that the higher levels of insulin damage brain white matter well before glucose and HgbA1c levels become elevated.

To investigate the relationship between insulin resistance and brain white matter (WM, myelinated axonal tissue) damage the authors correlated diffusion tensor imaging of the brains of 127 subjects age 41–86 years with insulin resistance as determined by the homeostasis model assessment of IR (HOMA-IR). There was indeed a significant association:

“Participants were divided into 2 groups based on HOMA-IR values: “high HOMA-IR” (≥2.5, n = 27) and “low HOMA-IR” (<2.5, n = 100)…The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity.”

In other words, regardless of age, higher insulin resistance predicted more abnormalities in the brain white matter. The authors conclude:

“In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults. “

Clinical note: It is imperative for practitioners to assess for insulin resistance well before HgbA1c and glucose become elevated.

Type 2 diabetes is associated with brain atrophy

Diabetes Care August 2013Type 2 diabetes subjects the brain to insult by high levels of both insulin and glucose. A study just published in the journal Diabetes Care shows that brain atrophy resembling Alzheimer’s disease exceeds cerebrovascular disease (brain ischemia and stroke) in type 2 diabetes. The authors determined to resolve whether cognitive dysfunction in T2DM was linked more to brain atrophy or vascular disease in the brain:

Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function.”

They examined 350 type 2 diabetes subjects with MRI and cognitive tests (and 363 controls without T2DM). With the MRI they mapped the regional distribution of brain atrophy. They also measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes), and looked for links with loss of cognitive function.

T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes but not with microbleeds or WMH [white matter hyperintensity]. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume.”

In other words, as the authors were quoted in Medscape Family Medicine:

“This study is the first to demonstrate that brain atrophy rather than cerebrovascular lesions may substantially mediate the relationship between [type 2 diabetes] and cognitive impairment.”

Additionally as noted in Medscape Family Medicine

Gray-matter atrophy associated with [type 2 diabetes] is widely and bilaterally distributed in hippocampi, temporal, frontal, and cingulate cortices and subcortical nuclei,” they summarize. “It appears to be the primary driver of cognitive dysfunction in people with [type 2 diabetes].”

Clinical note: Brain atrophy doesn’t occur overnight. Practitioners should bear in mind that early elevations of HgbA1c and other markers of insulin resistance are a risk factor for cognitive dysfunction associated with brain atrophy. Biological functions regulated by brain arousal and inhibition are also vulnerable. The authors conclude:

Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.”

Your brain controls your cholesterol level

Nature NeuroscienceYet another reason to ascertain the functional integrity of the brain and central nervous system for chronic degenerative disease and aging is presented in this interesting paper in the journal Nature Neuroscience. An editorial commenting on this study just published in Science Translational Medicine comments:

“Early on, it was thought that the cholesterol we eat is a major determinant of our circulating cholesterol levels, and many people tried to avoid eating cholesterol-rich foods like egg yolks, meat, and dairy products in order to lower their blood cholesterol. It turned out, however, that the amount of cholesterol we eat has only a modest impact on our blood cholesterol concentrations…Because the brain controls metabolic functions such as hepatic glucose production and lipid metabolism in fat, it is reasonable to think that the brain might also regulate the metabolic pathways that control circulating cholesterol. Now Perez-Tilve et al. have demonstrated in a series of studies that this is the case.”

The authors who performed the research state:

“We found that the CNS is also an important regulator of cholesterol in rodents. Inhibiting the brain’s melanocortin system by pharmacological, genetic or endocrine mechanisms increased circulating HDL cholesterol by reducing its uptake by the liver independent of food intake or body weight.”

In the course of their experiments they made this interesting observation”

“We found that the gut-brain control of cholesterol metabolism is independent of changes in food intake or body weight.”

Noting that the gut hormone ghrelin increased fat storage and cholesterol, they then determined that melanocortin in the brain controls ghrelin expression. They demonstrated that inhibiting melanocortin increased cholesterol by inhibiting its clearance from the bloodstream. They then showed that activating the brain melanocortin system decreased cholesterol levels. They conclude with this promising statement:

“…circulating levels of cholesterol are under remote, but direct, control of specific neuroendocrine circuits in the CNS…Direct or indirect pharmacological modulation of hypothalamic melanocortin tone may offer a potent way to treat hypercholesterolemia and to simultaneously target all major components of the metabolic syndrome.

Science Translational MedicineAnd the editorial further states:

“These findings also suggest that other brain signals—nutrients, emotions, and stress, for example—could also regulate cholesterol metabolism. This may be a mechanism through which alternative medicine practices such as acupuncture and aromatherapy could regulate cardiovascular risk factors. These techniques can modulate the autonomic nervous system, which is probably the main peripheral mediator of the brain control of cholesterol metabolism.”

This is another reason why regulating the central and autonomic nervous systems is a fundamental element in our approach to treatment, and why profiling the autonomic nervous system with heart rate variability analysis is so valuable.

DHA supplementation improves frontal brain activation and attention

Am Journal Clin NutritionThis study recently published in the American Journal of Clinical Nutrition provides more evidence for the importance of essential fatty acids for brain function. In this case the authors are interested in the effect of docosahexaenoic acid (DHA) supplementation on prefrontal cortex regulation of attention.

“Emerging evidence suggests that docosahexaenoic acid (DHA, 22:6n–3)…positively regulates cortical metabolic function and cognitive development…The objective was to determine the effects of DHA supplementation on functional cortical activity during sustained attention in human subjects.”

After giving the randomly assigned test cohort DHA supplements they compared cortical activation patterns during sustained attention with those given placebo by functional magnetic resonance imaging (fMRI).

What did their data show?

“At 8 wk, erythrocyte [red blood cell] membrane DHA composition increased significantly from baseline in subjects who received low-dose (by 47%) or high-dose (by 70%) DHA but not in those who received placebo (–11%). During sustained attention, both DHA dose groups had significantly greater changes from baseline in activation of the dorsolateral prefrontal cortex than did the placebo group…The erythrocyte DHA composition was positively correlated with dorsolateral prefrontal cortex activation…”

That last phrase is especially important: DHA is not the only fatty acid that is important for neuronal (brain cell) function. EPA, arachadonic acid and others also play important roles. How do we know with certainty whether someone needs supplementation, which fatty acid should it be, and how much? The Essential Fatty Acid Profile measures the red blood cell membrane content of fatty acids (and is equivalent to the neuronal membrane composition) that we use is the lab technology used by these investigators.

The authors’ conclusion:

“Dietary DHA intake and associated elevations in erythrocyte DHA composition are associated with alterations in functional activity in cortical attention networks during sustained attention in healthy boys.”

For any brain-related disorder we need to objectively answer the questions “What is the brain fatty acid composition? Are there any deficiencies or imbalances? Is supplementation indicated?” When needed, the correct fatty acid supplementation can result in dramatic improvements.

The brain’s role in obesity and the importance of dopamine

JAMAJAMA (the Journal of the American Medical Association) reports on research recently presented at the annual meeting of the Society for Neuroscience where researchers discussed their studies of the biological causes of overeating and obesity. One interesting comment of great practical importance: “Brain imaging of volunteers drinking a shake suggests that overweight persons with a gene variant associated with fewer dopamine receptors may be prone to impulsive eating.” Functional medicine patients know better than most people how important dopamine signalling is for calm contentment, focus, satisfaction, etc. and how deficits can result in compensatory compulsive behaviors and addictions that are in fact attempts to self-medicate. How do we fix dopamine signalling? By restoring the resources the body needs to manufacture its own dopamine and the brain’s capacity to respond to its stimulus.