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Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue

A 18F‐fluorodeoxyglucose positron emission tomography study

From the PET Program, Paul Scherrer Institute (Drs. Roelcke, Missimer, and Leenders, and R.P. Maguire), Villigen, Switzerland the Department of Neurology (Drs. Kappos, Lechner-Scott, Brunnschweiler, Huber, and Steck, Mr. Ammann, and Ms. Plohmann), Univ. Hospital, Basel, Switzerland; the Department of Neuroradiology (Drs. Dellas and Radü), Univ. Hospital, Basel, Switzerland; and the Department of Neurology (Dr. Leenders), Univ. Hospital, Zürich, Switzerland.

Abstract

To investigate the pathophysiology of fatigue in MS, we assessed cerebral glucose metabolism (CMR-Glu) in 47 MS patients using PET and 18F-fluorodeoxyglucose. Applying the Fatigue Seventy Scale (FSS), we first compared MS patients with severe fatigue (MS-FAT, n = 19, FSS > 4.9) and MS patients without fatigue (MS-NOF, n = 16, FSS < 3.7) on a pixel-by-pixel basis using Statistical Parametric Mapping (SPM95). Second, we compared FSS values of all 47 patients covering the whole range of this scale with CMRGlu using an analysis of covariance (SPM95). In addition, we determined global CMRGlu by region-of-interest analysis. Sixteen healthy subjects served as control subjects (CON). Global CMRGlu was significantly lower in both MS groups compared with CON (CON 43.3 ± 6.9 μmol/100 mL/min, MS-FAT 34.7 ± 4.4, MS-NOF 35.4 ± 4.5) but was not related to fatigue severity. Comparing the two MS groups, SPM95 analysis revealed predominant CMRGlu reductions bilaterally in a prefrontal area involving the lateral and medial prefrontal cortex and adjacent white matter, in the premotor cortex, putamen, and in the right supplementary motor area of MS-FAT. In addition, there were CMRGlu reductions in the white matter extending from the rostral putamen toward the lateral head of the caudate nucleus. FSS values were inversely related to CMRGlu in the right prefrontal cortex. CMRGlu in the cerebellar vermis and anterior cingulate was relatively higher in MS-FAT than in MS-NOF patients. CMRGlu of both regions showed positive correlations with FSS values. Our data suggest that fatigue in MS is associated with frontal cortex and basal ganglia dysfunction that could result from demyelination of the frontal white matter.

Positron emission tomography (PET) and [18F]-2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMRglc) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMRglcwere found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMRglc.

The beneficial effects of pioglitazone observed in this patient are somewhat unexpected as inflammation is less prominent in secondary progressive MS compared to relapsing remitting disease. However, improvements in upper body strength, coordination, dysphagia, and cognitive function, suggest neurological benefit associated with pioglitazone treatment. In addition to their anti-inflammatory actions, TZDs can also influence cell physiology in a receptor-independent manner, and we recently demonstrated that TZDs increase astrocyte glucose metabolism and lactate production [11]. It is therefore feasible that effects on brain metabolism, for example increased capacity of astrocytes to provide lactate to surrounding neurons, accounts in part for improved cognitive and motor function. However, the persistence of lower extremity paralysis appears a likely consequence of irreversible spinal cord atrophy.

Cece wrote:If Shilajit doesn't work, we could try pioglitazone.
http://www.jneuroinflammation.com/content/1/1/3

Pioglitazone worked like gangbusters for the SPMS patient in the article.

The beneficial effects of pioglitazone observed in this patient are somewhat unexpected as inflammation is less prominent in secondary progressive MS compared to relapsing remitting disease. However, improvements in upper body strength, coordination, dysphagia, and cognitive function, suggest neurological benefit associated with pioglitazone treatment. In addition to their anti-inflammatory actions, TZDs can also influence cell physiology in a receptor-independent manner, and we recently demonstrated that TZDs increase astrocyte glucose metabolism and lactate production [11]. It is therefore feasible that effects on brain metabolism, for example increased capacity of astrocytes to provide lactate to surrounding neurons, accounts in part for improved cognitive and motor function. However, the persistence of lower extremity paralysis appears a likely consequence of irreversible spinal cord atrophy.

cheerleader wrote:Interesting....Reduced glucose metabolism found in normals exposed to high altitude exposure....or chronic hypoxia. It was high altitude that really slammed Jeff before venoplasty. Even after acclimation, the hypometabolism remained.

Positron emission tomography (PET) and [18F]-2-deoxy-2-fluro-D-glucose (FDG) imaging techniques were used to assess regional cerebral glucose metabolic rates (rCMRglc) in six US marines (Caucasian lineage) before and after a 63-day training program for operations at high altitudes ranging from 10,500 to 20,320 ft. Significant changes in rCMRglcwere found for 7 of 25 brain regions examined. Significant decreases in absolute cerebral glucose metabolism after high-altitude exposure were found in five regions: three frontal, the left occipital lobe, and the right thalamus. In contrast, for the right and left cerebellum significant increases in metabolism were found. The magnitudes of these differences, in terms of absolute metabolism, were large, ranging from 10 to 18%. Although the results may not be solely the result of lower oxygen levels at high altitude, these findings suggest that the brain of healthy human lowlanders responds to chronic hypoxia exposure with precise, region-specific fine tuning of rCMRglc.

http://ajpregu.physiology.org/content/277/1/R314.full

Flying—Flying is by far the most frequent cause of brief everyday hypoxia. Although they might reach altitudes of 30,000-45,000 feet, the cabins of commercial aircraft are kept at a pressure equivalent to an altitude of between 5,000 and 7,500 feet. For the average passenger flying for a few hours at this altitude, the effects are rather mild. A sensitive person may notice slight shortness of breath; occasional irregular breathing; periodic breathing; and some feeling of uneasiness or discomfort. Those who have a tendency to hyperthyroidism, or those with a mild anemia or a pulmonary-cardiac condition may notice the altitude more. Individuals who are at risk for or have a sickle trait, such as sickle cell anemia, should consult a doctor before flying, as lack of oxygen makes red blood cells more fragile.

It is important to note that when hypoxia is discussed in terms of altitude, it is pressure altitude, not density altitude, that matters. There is always plenty of oxygen around — a whole atmosphere of it — but what controls the amount that reaches the brain is pressure differences across various membranes in the body. The process by which oxygen reaches the brain is affected by a great many factors that vary widely among individuals. By some definitions, normal people acclimatized to sea level begin to be hypoxic at 7,000 feet or so.

Technology Insights of Oxygen Metabolic Abnormalities in MS (Yulin Ge, USA)
The role of vascular pathology in multiple sclerosis (MS) was suggested long ago by Ribbert (1882) and Putnam (1933). With the invention and advances of imaging technology, now there is accumulating evidence in vivo of primary vascular pathogenesis and hemodynamic impairment in MS. In particular, there is cerebral blood perfusion changes in lesions and normal appearing brain tissues, suggesting there might be an ischemic and/or hypoxic origin of MS disease. In this presentation, I am going to discuss the hemodynamic perfusion changes and vascular abnormalities measured with several advanced MRI techniques and their pathophysiological significance in MS. First, the close perivenous relationship of MS lesions associated with the underlying vascular inflammatory changes can be evaluated with high resolution susceptibility-weighted imaging. Second, cerebral blood perfusion changes including cerebral blood volume (CBV) and flow (CBF) have been evaluated with dynamic susceptibility contrast-enhanced (DSC) and arterial spin labeling (ASL) MRI techniques. The lesions showed different patterns of perfusion change despite that hypoperfusion is a general feature seen in MS tissues. The perfusion changes in MS may provide additional information of microvascular abnormalities. Third, the recent promising vascular ischemic / hypoxic hypothesis can be evaluated in vivo with several techniques including perfusion- and diffusion- weighted imaging during the acute phase and oxygen metabolic measures as well as functional MRI techniques. In summary, there is increased awareness from both histopathologic and imaging studies of the role of microvascular and hemodynamic impairment in tissue injury in MS; therefore, targeting hypoxic injury may be indicated in the new therapeutic strategy.

A hypoxia-like condition has been evidenced in patients with multiple sclerosis (MS). Perfusion MRI is particularly relevant to studying MS pathogenesis because it has been shown that hypoperfusion of the brain parenchyma in MS patients may precede disease onset. MS patients show abnormal blood flow perfusion patterns, such as increased mean transit time (MTT), and decreased cerebral blood flow (CBF) and cerebral blood volume (CBV) within normal appearing white matter (WM) and gray matter (GM). Perfusion MRI abnormalities are present from the earliest stages of the disease in normal appearing WM, while GM perfusion changes were evidenced at later disease stages. In fact progressive MS patients show more severe perfusion changes compared to relapsing MS. Chronic inflammatory events related to local blood congestion and secondary hyperemia of the brain parenchyma are proposed as a cause of these hemodynamic abnormalities detected on perfusion MRI in patients with MS. The hemodynamic abnormalities detected on perfusion MRI in patients with MS are currently interpreted as being a consequence of chronic inflammatory events related to local blood congestion and secondary hyperemia of the brain parenchyma. Furthermore, at this time it is not clear whether reduced perfusion of the brain parenchyma in MS patients is a sign of vascular pathology or decreased metabolic demand. Alternatively, it can be hypothesized as a disorder that involves the major vasoactive substances. Increased perfusion in the area of lesion formation could be a sign of vessel dilation mediated by pro-inflammatory cytokines. Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition described in MS patients, characterized by multiple intra- and extra-luminal stenosing malformations of the principal pathways of extra-cranial venous drainage. An altered perfusion pattern may not only be a consequence of local circulatory disturbances due to inflammatory mechanisms in acute or chronic phases, but rather could result from an outflow blockage situated far away from the lesions. CCSVI may impact local hemodynamics at places distant from the location of the mechanical stenosis, as in any condition of venous obstruction of the major trunks. Such a mechanism may lead to capillary hypertension and leakage, consistently contributing to inflammation. Preliminary findings are presented from a pilot study investigating the relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma.

This increase in blood pressure fluctuation at the venule end of the capillary bed, which would be equivalent to local hypertension, is predicted to reduce the pressure drop across the bed which, in turn, would reduce blood flow through the bed in accordance with Darcy’s Law. Such a reduction in blood flow through the bed would be accompanied by a reduction in the transfer of oxygen, glucose and other nutrients into the brain tissue in accordance with Fick’s Principle. The reduction in oxygen levels in the brain tissue (i.e. hypoxia), would, in turn, be associated with increased fatigue and decreased mental acuity in the subject patient. In addition, cerebral hypoxia may be associated with vasoconstriction of the endothelium and promotion of both leukocyte- endothelial adherence and angiogenesis (ie. growth of collateral veins). The deprivation of oxygen adjacent to the venules may also result in cell death, including endothelial, and oligodendrocyte cells.

MarkW wrote:The first question to ask and get a result for is:
-Does destenosis of all instances of CCSVI syndrome reverse this ???

Taurus wrote:Please see that Sillajit is high in iron content which may be bad for persons with CCSVI. Anybody with MS who has tried Sillajit, please comment.

Gases. Gases such as CO2, O2 and volatile anesthetics diffuse rapidly into the brain. As a consequence, the rate at which their concentration in the brain comes into equilibrium with plasma is limited primarily by the cerebral blood flow rate.

The brain is metabolically one of the most actice of all organs in the body. The brain does not store excess energy and derives almost all of its energy needs from aerobic oxidation of glucose. Therefore, it requires a continuous supply of glucose and oxygen to meet its energy requirements.

Figure 11.10 shows there is an excellent correlation between the amount of glucose uses and local cerebral blood flow. Regulation of blood flow to a brain area is achieved by control of dilation of cerebral vessels.

Considering
the earliest legion of MS is microvascular and
considering the ease with which microvessels may
be isolated from MS human autopsy brain plaque
tissue (Pardridge et al, 1987; Washington et al,
1994), it is somewhat surprising that there are so
few studies on the immunology and biochemistry of
capillaries isolated from MS plaque tissue.

Dick et al.4 estimated that capillary endothelial cells in the brain transport about 10 times their weight of glucose per minute to support the glucose requirements of the brain

Normally, the transport of glucose across the blood–brain barrier is not rate-limiting, and about 50 percent of the glucose transported diffuses back into the blood. The intracellular phosphorylation of glucose to glucose-6-phosphate is the rate-limiting event for cerebral glycolysis.