Tuesday, March 25, 2008
Lipid rafts, protein scaffold and neurologic disease
Benarroch EF. Neurology 2007; 69: 1635-1639.
Review article. Lipid rafts are specialized microdomains of the plasma membrane involved in vesicular transport and signalling mechanisms. They are encoded in cholesterol, sphingolipids, and scaffolding prteins such as caveolins and septins. Mutation of caveolin-3 is associated with diverse muscle disorders. Lipid rafts may be the site of abnormal processing of APP and prion protein.. Impaired septin-4 function can lead to synuclein accumulation and neurotoxicity in Parkinson's disease.
Lipid rafts are also characterized by their interactions with the cytoskeleton. Caveolin and flotillin act as scaffolding proteins that recruit signalling proteins into lipid rafts. Cholesterol depletion disrupts lipid rafts, leading to decreased accunulation and uptake of glutamate, GABAm or serotonin transporters. Caveolin 3 colocalizes with dysferlin. Mutations of CAV# are linked to limb girdle dystrophy 1C, rippling muscle disease, hyperCKEemia, distal myopathy, and a recessive form of LGD. Septin 4 is a component of the presynaptic scaffold in dopaminergic neurons projecting to the striatum.
Sunday, February 3, 2008
Serum uric acid and brain ischemia in normal elderly adults
Schretlen DJ, Inscore AB, Vannorsdall TD et al. Neurology 2007; 69:1418-1423.
The authors make the case for uric acid in brain function/dysfunction. UA is a natural antioxidant, with concentrations tenfold those of Vitamins c and e. Low UA is found in patients with MCI AD and PD. High UA predicts better outcome after stroke in one study (see Chamorro, Stroke, 2002) and in experimental models. However high UA also predicts occurrence of stroke, second stroke, fatal MI. Allopurinol protects against stroke damage in an animal model, and high UA correlates with HTN, atherosclerosis, type 2 DM and the metabolic syndrome. Studies show elderly participants with higher UA levels were 2.7 to 5.9 times more likely to be in the lowest quartile of processing speed, verbal and working memory.
In the present study, patients with higher UA were more likely to have increased volume of WMHs on brain MRI. There was a 4-5 x increased likelihood if having excessive ischemic burden.
The authors speculate that UA can be prooxidant as well as anti-oxidant.
This blogger, a skeptic, believes that high UA is a marker for dehydration and capillary sludging and that hydrating the elderly is a good way to reduce stroke. Therefore, aside from its biologic properties, UA is just a marker for the state of hydration. These authors from jhmi (johns hopkins) did not appreciate or address this obvious clinical point.
Postscript--review article Feig DI, Kang DH, Johnson RH NEJM 2008;359:1811-1821 "Uric acid and cardiovascular risk" also reviews subject from a different vantage point. They note Framingham does not currently consider urate a risk factor. This is a nice review article with lots of good references.
The authors make the case for uric acid in brain function/dysfunction. UA is a natural antioxidant, with concentrations tenfold those of Vitamins c and e. Low UA is found in patients with MCI AD and PD. High UA predicts better outcome after stroke in one study (see Chamorro, Stroke, 2002) and in experimental models. However high UA also predicts occurrence of stroke, second stroke, fatal MI. Allopurinol protects against stroke damage in an animal model, and high UA correlates with HTN, atherosclerosis, type 2 DM and the metabolic syndrome. Studies show elderly participants with higher UA levels were 2.7 to 5.9 times more likely to be in the lowest quartile of processing speed, verbal and working memory.
In the present study, patients with higher UA were more likely to have increased volume of WMHs on brain MRI. There was a 4-5 x increased likelihood if having excessive ischemic burden.
The authors speculate that UA can be prooxidant as well as anti-oxidant.
This blogger, a skeptic, believes that high UA is a marker for dehydration and capillary sludging and that hydrating the elderly is a good way to reduce stroke. Therefore, aside from its biologic properties, UA is just a marker for the state of hydration. These authors from jhmi (johns hopkins) did not appreciate or address this obvious clinical point.
Postscript--review article Feig DI, Kang DH, Johnson RH NEJM 2008;359:1811-1821 "Uric acid and cardiovascular risk" also reviews subject from a different vantage point. They note Framingham does not currently consider urate a risk factor. This is a nice review article with lots of good references.
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