High-Fat Diet-Induced Diabetic Conditions Exacerbate Cognitive Impairment in a Mouse Model of Alzheimer's Disease Via a Specific Tau Phosphorylation Pattern.

BACKGROUND: Epidemiological evidence has demonstrated a clear association between diabetes mellitus and increased risk of Alzheimer's disease (AD). Cerebral accumulation of phosphorylated tau aggregates, a cardinal neuropathological feature of AD, is associated with neurodegeneration and cognitive decline. Clinical and experimental studies indicate that diabetes mellitus affects the development of tau pathology; however, the underlying molecular mechanisms remain unknown. OBJECTIVE: In the present study, we used a unique diabetic AD mouse model to investigate the changes in tau phosphorylation patterns occurring in the diabetic brain. DESIGN: Tau-transgenic mice were fed a high-fat diet (n = 24) to model diabetes mellitus. These mice developed prominent obesity, severe insulin resistance, and mild hyperglycemia, which led to early-onset neurodegeneration and behavioral impairment associated with the accumulation of hyperphosphorylated tau aggregates. RESULTS: Comprehensive phosphoproteomic analysis revealed a unique tau phosphorylation signature in the brains of mice with diabetic AD. Bioinformatic analysis of the phosphoproteomics data revealed putative tau-related kinases and cell signaling pathways involved in the interaction between diabetes mellitus and AD. CONCLUSION: These findings offer potential novel targets that can be used to develop tau-based therapies and biomarkers for use in AD.

Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy.

Impairment of cardiac function in ischemic cardiomyopathy has been postulated to be due to the decrease in blood flow and increase in collagen synthesis. Therefore, an approach to alter them directly by means of a growth factor may open up a new therapeutic concept in ischemic cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with angiogenic and antifibrotic effects. Thus, we examined the feasibility of gene therapy using HGF plasmid DNA for ischemic cardiomyopathy. Human HGF plasmid DNA at a dose of 0.4 or 4 mg was injected into ischemic myocardium of pigs induced by ameroid constrictor with the NOGA system. At 1 month after injection, the ischemic area was significantly reduced in the HGF group, accompanied by a significant increase in capillary density and regional myocardial perfusion in the ischemic area (P<0.01). In contrast, a significant decrease in fibrotic area was observed in the HGF group, associated with a significant decrease in collagen I, III and TGF-beta synthesis as compared to the control group (P<0.01). Consistently, cardiac function was significantly improved in the 4 mg HGF group as compared to the control group (P<0.05). Overall, the present in vivo experiments demonstrated that intramyocardial injection of human HGF plasmid DNA in ischemic cardiomyopathy resulted in a significant improvement in cardiac function through an increase in blood flow and decrease in fibrosis. These favorable outcomes suggest potential utility to treat patients with ischemic heart disease using HGF gene transfer. Currently, a phase I study using human HGF plasmid DNA is ongoing to test the validity of this concept.

Increase in extracranial atherosclerotic carotid lesions in patients with brain ischemia in Japan. An angiographic study.

BACKGROUND AND PURPOSE: Atherosclerotic lesions in the cerebral arteries are distributed heterogeneously among different races. Intracranial carotid lesions are reported to be more common than extracranial carotid lesions among Japanese people, which is in sharp contrast to the pattern of cerebral atherosclerosis in whites. However, several Japanese clinicians have the impression, which has yet to be clinically proven, that extracranial carotid diseases are recently increasing in number. METHODS: One hundred twenty-one patients who developed ischemic stroke and underwent angiography were examined in the study. Seventy were admitted to our clinic from 1963 to 1965 (early group); the remaining 51 patients were seen from 1989 to 1993 (recent group). Angiographic findings and vascular risk factors were compared between the two groups. RESULTS: Severe atherosclerotic lesions of the extracranial internal carotid arteries increased significantly during the ensuing 24 years between the end of the first period until the beginning of the second period (from 1965 to 1989), whereas lesions in the intracranial carotid system were similar between the two groups. Severe atherosclerosis in the extracranial internal carotid artery was more frequent in patients with diabetes mellitus, which proved to be the only risk factor that showed a temporal increase. CONCLUSIONS: The proportion of severe atherosclerosis in Japanese patients with brain ischemia has been increasing in the extracranial internal carotid artery, while that in the intracranial carotid system remains unchanged. Such a temporal change may be the result, at least in part, of an increase in the prevalence of diabetes mellitus.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: incidence of stroke in Japan and Hawaii.

As part of the Ni-Hon-San Study, stroke incidence was compared in the Japan and Hawaii cohorts. Stroke cases were classified in two types, intracranial hemorrhage (ICH) and thrombo-embolic stroke (T-E). For each type the incidence in Japan was about three times as great as in Hawaii. The ratio ICH/T-E was 1/2.2 and 1/1.6 in Japan and Hawaii, respectively. Blood pressure was the most important risk factor, followed by age for total stroke in both Japan and Hawaii. Proteinuria was also a risk factor in Hawaii. Conversely, an index of animal food intake was inversely related to total stroke, significantly in Hawaii, and at a suggestive level for total and hemorrhagic stroke in Japan. Since the levels of blood pressure do not differ between Japan and Hawaii, one possible explanation for the large difference in stroke incidence between the two cohorts may be the fact that animal protein and saturated fat intake, which is inversely associated with stroke incidence, is much greater in Hawaii than in Japan. This explanation would support epidemiologic and experimental studies in Japan which suggest that dietary animal protein and fat exert an inhibitory effect on the incidence of stroke.

Catecholamines, angiotensin II and sodium concentrations in cerebrospinal fluid in young men with borderline hypertension.

To evaluate the role of central nervous mechanisms and their relationships to the peripheral sympathetic nervous system in borderline hypertension, we measured catecholamines, angiotensin II (AII) and sodium (Na) concentrations in cerebrospinal fluid (CSF) with plasma catecholamines concomitantly in 12 young men with borderline hypertension and 7 age-matched healthy normotensive men on ordinary salt intake. Plasma norepinephrine (NE) and epinephrine (E) were higher in the borderline hypertensives than in the normotensives (NE: 239 +/- 15 vs 190 +/- 11 pg/ml, p less than 0.05, E: 83 +/- 9 vs 43 +/- 6 pg/ml, p less than 0.01). NE levels in CSF were also higher in the borderline hypertensives than in the normotensives (200 +/- 15 vs 150 +/- 18 pg/ml, p less than 0.05). In most of the subjects, CSF E and plasma and CSF dopamine levels were below the sensitivity of the assay. CSF NE correlated positively with both plasma NE (p less than 0.01) and mean blood pressure (p less than 0.05) in all subjects. Immunoreactive AII and Na concentrations in CSF did not differ between the borderline hypertensives and normotensives. These results suggest that peripheral sympathoadrenal overactivity in young subjects with borderline hypertension may be related to an altered function of central noradrenergic neurons. AII and Na in the central nervous system do not appear to have an important role in borderline hypertension.

Elevated plasma catecholamines without alteration in cardiovascular responsiveness in young men with borderline hypertension.

Plasma catecholamines and cardiovascular responses to upright posture, exogenous noradrenaline (NA), and isoproterenol (IP) were examined in 20 young men with borderline hypertension and in 10 age-matched normotensive volunteers. Resting plasma NA and adrenaline (Ad) levels were higher in the borderline hypertensive patients. Significant correlations were found among plasma NA and mean blood pressure (MBP) or heart rate (HR), and between plasma Ad and HR in all individuals in the supine position. The increases in plasma NA were similar between groups for orthostatic positions. Pressor response to exogenous NA and chronotropic response to exogenous IP were not augmented in borderline hypertensives. A negative correlation was found between plasma NA before infusion and the increases of MBP produced by NA or the increases of HR produced by IP in all the individuals. Our observations suggest that there is hyperactivity of the sympathoadrenal system without enhancement in cardiovascular reactivity to catecholamines in young men with borderline hypertension.

Augmented sympathetic nervous function in young subjects with borderline hypertension.

In order to elucidate the mechanism of blood pressure elevation in the patients with borderline hypertension, the sympathetic nervous activity was investigated and the following results were obtained: 1) Plasma catecholamine (CA) levels were elevated in young men but not in middle-aged men with borderline hypertension in comparison with age-matched normal men. 2) Cardiovascular responsiveness to exogenous CA was not augmented in young men with borderline hypertension. 3) Cerebrospinal fluid noradrenaline levels were elevated in young men with borderline hypertension. They correlated positively with plasma NA or blood pressure. 4) In young men with borderline hypertension, plasma and urinary CAs were not altered by hypertonic saline loading. These results suggest that increased activity of the central and peripheral sympathetic nervous system is an important mechanism of blood pressure elevation in young subjects with borderline hypertension.

[Long-term prognosis of cerebral infarction--influence of arterial stenotic lesion for survival (author's transl)].

Cerebral four vessel angiography was performed in 85 patients with non-embolic cerebral infarction and followed for ten years. Of 45 patients with arterial stenosis of 25 per cent or more, 21 (46.7%) survived at 5 years and 12 (26.7%) at 10 years after onset of the stroke. In contrast, survivors of 45 patients with stenosis less than 25 per cent or with no stenotic lesion, were 35 (87.5%) at 5 years and 29 (72.5%) at 10 years after the onset. The survival rate of the former patients group was lower significantly than the expected survival rate in a general population. Arterial stenosis of 25 per cent or more suggested a trend of poor prognosis in patients with multiple stenosis, especially those of bilateral internal carotid arteries, and of better prognosis in patients with stenosis in vertebrobasilar system. Patients with stenosis of 50 per cent or more in sphenoidal portion of the middle cerebral artery seemed to have a poor prognosis than those in the internal carotid artery.

Effect of carotid artery ligation on regional cerebral blood flow in normotensive and spontaneously hypertensive rats.

Regional cerebral blood flow (rCBF) was measured in normotensive rate (NTR) and spontaneously hypertensive rats (SHR), in a lightly anesthetized state and with control of PaCO2 by artificial ventilation. Without carotid artery ligation, NTR and SHR showed almost identical rCBF values and distribution, despite significantly elevated levels of blood pressure in SHR. Bilateral carotid artery ligation, however, caused much more pronounced decreases of rCBF (ischemia) in SHR than NTR, in regions supplied by the carotid artery. The reduction of rCBF in SHR was rather homogenous and symmetrical. Mechanisms causing the differences between NTR and SHR are discussed.

Prognosis of occlusive cerbrovascular diseases in normotensive and hypertensive subjects.

Comparison of the clinical features, especially prognosis, in cerebral infarction was made between nine normotensive subjects and 16 hypertensive patients with an 80% stenosis or occlusion of the intracranial or extracranial arteries. Our own criteria for evaluating hypertension were employed on the basis of the following items: a past history of hypertension, blood pressure levels on admission and during hospitalization, degree of retinopathy, and ECG changes. In 17 of 25 cases, brain circulation was measured by the intravenous RISA technique. Abnormalities of the EEG and reduction of cranial blood flow were greater, and an early prognosis for neurological deficits in the first two months after the onset of stroke was poorer in the hypertensive group than inthe normotensive group. These results are contradictory to the observations of others.