Effect of thrombin inhibition in vascular dementia and silent cerebrovascular disease. An MR spectroscopy study.
OBJECTIVE
Silent cerebrovascular disease (CVD) has been proposed as a predisposing condition for clinically overt stroke and vascular dementia. Recently, we found increased thrombin generation in silent CVD patients. Here, we report the effect of thrombin inhibition using a potent selective thrombin inhibitor on the cerebral metabolism and function in peripheral arterial occlusive disease (PAOD) patients with or without silent CVD.


METHODS
We examined 17 mild chronic PAOD patients, including 2 cases of vascular dementia. We divided the patients into 2 groups: 1 was the advanced CVD group with multiple lacunar infarction and/or advanced periventricular hyperintensity detected by brain MRI (n=12), and the other was the no CVD group that had none of these abnormalities (n=5). We assessed the cerebral biochemical compounds in the deep white matter area and cerebellar hemisphere (8 cm3) by proton MR spectroscopy before and after infusion of argatroban (10 mg/d IV) over 2 hours for 7 days.


RESULTS
The ratio of N-acetylasparate (NAA) to total creatine (Cre) in the deep white matter area was significantly lower in the advanced CVD group than in the no CVD group, whereas there were no significant differences in this ratio in the cerebellar hemisphere between the 2 groups. In the former group, this decreased NAA/Cre ratio significantly increased after argatroban therapy, whereas there was no change in the latter group. The 2 patients with vascular dementia showed clinical improvement with marked increases in the NAA/Cre ratio and mini-mental score.


CONCLUSIONS
These results suggest that increased thrombin generation may have some pathophysiological roles in developing vascular dementia and its chronic predisposing conditions. Thrombin inhibition may break this vicious cycle and lead to clinical improvement.
Kario
K
K
Department of Cardiology, Jichi Medical School, Tochigi, Japan.
Matsuo
T
T
Hoshide
S
S
Umeda
Y
Y
Shimada
K
K
D000368:Aged; D000990:Antithrombin III / Q000032:analysis; D000991:Antithrombins / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000032:analysis; D015415:Biomarkers; D001777:Blood Coagulation; D001923:Brain Chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism; D002560:Cerebrovascular Circulation; D003071:Cognition / Q000502:physiology; D003401:Creatine / Q000032:analysis; D015140:Dementia, Vascular / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D004792:Enzyme Precursors / Q000032:analysis; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D010875:Pipecolic Acids / Q000008:administration & dosage*; D011522:Protons; D013449:Sulfonamides; D013917:Thrombin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000991:Antithrombins; D015415:Biomarkers; D004792:Enzyme Precursors; D010875:Pipecolic Acids; D011522:Protons; D013449:Sulfonamides; D001224:Aspartic Acid; D000990:Antithrombin III; D001120:Arginine; C000179:N-acetylaspartate; D013917:Thrombin; C026812:meizothrombin; C031942:argatroban; D003401:Creatine