Association of postural instability with asymptomatic cerebrovascular damage and cognitive decline: the Japan Shimanami health promoting program study.

BACKGROUND AND PURPOSE: Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387). METHODS: Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain MRI. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography. RESULTS: Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002). CONCLUSIONS: Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects.

Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study.

BACKGROUND/AIM: Lower body weight in later life has been shown to be associated with dementia. However, abdominal fat distribution under conditions of mild cognitive impairment (MCI) and the possible involvement of leptin and adiponectin in MCI have not been fully investigated. METHODS: We analyzed 517 middle-aged-to-elderly community-dwelling persons. Abdominal subcutaneous fat and visceral fat areas were determined using computed tomography, and plasma leptin and adiponectin concentrations were measured in fasting samples. MCI was assessed using the Japanese version of the MCI screening method. RESULTS: In men, the abdominal subcutaneous fat area was significantly lower in participants with MCI than in those with normal cognitive function [median (interquartile range): 107.4 (85.9, 133.1) cm² vs. 136.4 (93.1, 161.4) cm²; p = 0.002]. Logistic regression analyses with confounding factors including age and abdominal subcutaneous fat area showed that a 10 mg/l increase in plasma adiponectin had a protective effect against the development of MCI in men (odds ratio: 0.46; 95% CI: 0.20-0.97; p = 0.041). In contrast, MCI was not found to be associated with abdominal fat area or adipose-derived hormones in women. CONCLUSION: Reduced amounts of subcutaneous fat and low levels of plasma adiponectin were found to be associated with MCI in men.

Postural instability is associated with brain atrophy and cognitive impairment in the elderly: the J-SHIPP study.

BACKGROUND/AIMS: Mobility impairment in older adults has been suggested to be a marker of subclinical structural and functional brain abnormalities. We investigated a possible association between static postural instability and brain abnormalities and cognitive decline. METHODS: The study subjects were 390 community residents without definitive dementia (67 +/- 7 years old) and 21 patients with Alzheimer's disease (AD). Brain atrophy was measured by MRI. RESULTS: The mobility of the posturography-measured center of gravity (COG) was positively associated with the temporal horn area (THA; r = 0.260; p < 0.001). Subjects who could not stand on one leg for >40 s (n = 102) showed a significantly larger THA (22 +/- 18 vs. 14 +/- 11 x 10(-2) cm(2); p < 0.001). Multiple regression analysis identified COG path length (beta = 0.118; p = 0.032) and one-leg standing time (beta = 0.176; p = 0.001) as independent determinants of THA. Mild cognitive impairment (MCI) subjects (n = 61) had a significantly enlarged THA compared to that of normal cognitive subjects (22 +/- 16 vs. 16 +/- 13 x 10(-2) cm(2); p = 0.002). AD patients showed a more enlarged THA (78 +/- 55 x 10(-2) cm(2)). Subjects with cognitive decline showed a significantly shorter one-leg standing time (normal: 50 +/- 17 s; MCI: 42 +/- 21 s; AD: 18 +/- 20s; p < 0.001). CONCLUSION: Reduced postural stability was an independent marker of brain atrophy and pathological cognitive decline in the elderly.

[Case of recurrent transverse myelitis and diplopia after meningomyeloradiculitis caused by Epstein-Barr virus].

A 60-year-old woman was admitted to our hospital because of pyrexia, headache, gait disturbance, and sensory disturbance in the lower part of the body four days after she received an epidural block for postherpetic neuralgia. Neurological tests revealed neck stiffness, flaccid paraparesis in the legs with absent deep tendon reflexes, and hyperesthesia below Th7. According to a cerebrospinal fluid examination, the protein concentration was 245 mg/dl and the cell count was 176/mm3. PCR analysis of the cerebrospinal fluid was positive for Epstein-Barr virus (EBV). Serological tests for EBV yielded mild increases of serum IgG antibodies against EBV nuclear antigen (EBNA) and IgG antibodies against EBV viral capsid antigen (VCA). In a spinal MRI, the inferior lumbar meninges showed gadolinium enhancement. Nerve conduction studies revealed a decreased F wave ratio in the bilateral tibial nerves. The patient was diagnosed with meningomyeloradiculitis caused by EBV. The symptoms improved after steroid pulse therapy, but relapses of transverse myelitis and diplopia due to disturbance of the bilateral abducent nerves and left trochlear nerve occurred 7, 12, 16, and 26 months after treatment. The relapses were sometimes accompanied by small fluctuations in cerebrospinal fluid protein concentration, cell count, or serum anti-EBV antibody titer. These findings suggest that the myelopathy and diplopia were induced by a secondary immune reaction after inflammation caused by EBV infection.

CDH13 genotype-dependent association of high-molecular weight adiponectin with all-cause mortality: the J-SHIPP study.

OBJECTIVE: Despite its anti-inflammatory and antiatherogenic effects, adiponectin is potentially associated with adverse clinical outcomes, such as all-cause mortality. As plasma adiponectin levels are strongly influenced by single nucleotide polymorphisms in the gene encoding T-cadherin (CDH13), we conducted a longitudinal study to investigate the possible link between the CDH13 genotype, plasma adiponectin levels, and all-cause mortality. RESEARCH DESIGN AND METHODS: This longitudinal study evaluated 2,020 Japanese subjects. Baseline clinical parameters were obtained from subjects' personal health records as evaluated at annual medical check-ups. Plasma high-molecular weight adiponectin (HMWA) levels were measured by an ELISA assay, and genotyping was performed by a TaqMan probe assay. RESULTS: Mean follow-up duration was 6.5 years. Kaplan-Meier analysis showed that HMWA levels were positively associated with mortality (P < 0.001). HMWA levels were associated with older age, lower body weight, lower plasma triglyceride and glucose levels, and higher plasma HDL cholesterol. However, the Cox regression analysis showed that the positive association between HMWA and all-cause mortality was independent of these covariates (hazard ratio [HR] 1.92, P = 0.006). The CDH13 rs4783244 genotype was strongly associated with baseline HMWA levels (per-allele effect size 1.65 µg/mL, P < 0.001). In a separate analysis by the CDH13 genotype, the HR for all-cause mortality was linearly increased with the number of G alleles (P value for HMWA-CDH13 genotype interaction = 0.023). CONCLUSIONS: Higher plasma HMWA level was an independent prognostic factor for all-cause mortality in a general population. The CDH13 genotype may be a factor that affects not only the plasma level of HMWA but also the prognostic significance of HMWA.

Postprandial hypotension as a risk marker for asymptomatic lacunar infarction.

OBJECTIVE: Increasing blood pressure (BP) variability is reported to be a cardiovascular risk factor. However, the clinical implications of postprandial hypotension (PHYPO), a commonly observed BP variability in elderly persons, are poorly understood. Here, we investigated the possible associations between postprandial BP decline and asymptomatic cerebral damage in community residents. METHODS: Study participants consisted of 1308 general community residents (65 ±â€Š9 years old). Postprandial BP change was calculated from SBP measured just before and 30 min after lunch. PHYPO was defined as a decline in SBP of more than 20 mmHg. The presence of asymptomatic cerebrovascular damage was evaluated by brain MRI. RESULTS: Prevalence of lacunar infarction was significantly higher in participants with PHYPO (P = 0.004). A postprandial decline in SBP was linearly increased with the number of lacunar lesions (none, n = 1200, -3.4±â€Š11.3 mmHg; one lesion, n = 82, -5.2 ±â€Š11.8; two lesions, n = 18, -6.9 ±â€Š11.5; three lesions, n = 7, -13.4 ±â€Š11.3; and four lesions, n = 1, -27; P = 0.012). Although participants with PHYPO were older (P < 0.001) and had higher preprandial BP (P < 0.001) and faster pulse wave velocity (P = 0.001), multivariate analysis adjusted for these covariates indicated that postprandial BP decline was an independent determinant for the number of lacunar infarctions (P = 0.004). No significant associations were observed with grade of periventricular hyperintensity or frequency of microbleeds. These relationships were also found in an analysis based on central BP, whereas no superiority was seen in the analysis based on central BP. CONCLUSION: Postprandial BP decline is an overlooked risk marker for asymptomatic lacunar infarction in community residents.

Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: the J-SHIP and Toon Health Study.

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2±0.7, Q2: 2.0±0.7, Q3: 1.9±0.7, Q4: 1.8±0.6, p<0.001) and insulin resistance (1.0±0.6, 1.2±0.7, 1.3±0.8, 1.5±1.0, p<0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (ß=-0.074, p=0.019) and insulin resistance (ß=0.115, p<0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p=0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r=-0.250, p<0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p=0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.

Liver enzyme and adipocytokine profiles are synergistically associated with insulin resistance: the J-SHIPP study.

AIM: Alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) are associated with insulin resistance and arteriosclerotic disease. Since adiposity raises liver enzyme levels and causes insulin resistance, adipocytokines are thought to underlie the relationship between liver enzymes and insulin resistance. To clarify this hypothesis, we conducted a cross-sectional epidemiological study in a Japanese general population. METHODS: The study subjects were 903 middle-aged to elderly persons. Plasma levels of adiponectin and leptin were measured, while other clinical parameters were obtained from personal health records of medical check-ups. Insulin resistance was assessed by a homeostasis model assessment index (HOMA-IR). RESULTS: Plasma levels of ALT (r=0.379, p<0.001), GGT (r=0.225, p<0.001), adiponectin (r= -0.346, p<0.001) and leptin (r=0.369, p<0.001) were significantly correlated with insulin resistance even on subgroup analysis by sex. Further, any combination of liver enzymes and adipocytokines was synergistically associated with insulin resistance (p<0.001) after adjustment for possible covariates (ALT*adiponectin: ß=-0.098, p<0.001, ALT*leptin: ß=0.129, p<0.001, GGT*adiponectin: ß=-0.054, p=0.054, GGT*leptin: ß=0.126, p<0.001); however, in simple obese subjects with normal adipocytokine levels, liver enzymes were not associated with insulin resistance (mean HOMA-IR: worsened adipocytokine +/visceral obesity +, 2.01±1.14; +/-, 1.39±0.84; -/+, 1.23± 0.55; -/-, 1.03±0.57; p<0.001). CONCLUSION: Plasma levels of ALT and GGT were independent determinants of insulin resistance only in subjects with a worsened adipocytokine profile. Use of liver enzyme levels as a marker of insulin resistance requires stratification by adipocytokine profile.

Postprandial hypertension, an overlooked risk marker for arteriosclerosis.

OBJECTIVE: Increased blood pressure (BP) variability is suggested to be a risk factor for cardiovascular disease. Although a postprandial decline in BP is a frequently observed phenomenon in the elderly, little attention has been paid to the clinical and diagnostic significance of postprandial BP change. Here, we aimed to clarify the possible association between postprandial BP dysregulation and arteriosclerosis. METHODS: The study subjects were 1339 apparently healthy middle-aged to elderly persons (66 ± 9 years old). Postprandial changes in BP were calculated by two readings on the same day, one just before lunch with a standardized Japanese meal and the second 30 min after lunch. Arteriosclerosis was assessed by carotid intima-media thickness and brachial-to-ankle pulse wave velocity. RESULTS: Mean preprandial and postprandial systolic BP was 127 ± 18 and 123 ± 18 mmHg respectively. One hundred and twelve subjects (8.4%) showed a greater than 20-mmHg postprandial decline in systolic BP, while 129 (9.6%) showed a greater than 10-mmHg increase. Arteriosclerosis was significantly higher in both postprandial hypotensive and hypertensive subjects. The postprandial changes in systolic BP were strongly associated with preprandial systolic BP (r = 0.335, p < 0.001). The association between postprandial hypotension and increased arteriosclerosis was therefore lost after adjustment for basal systolic BP. Multiple linear regression analysis adjusted for possible covariates, including basal BP, identified a postprandial increase in BP as an independent determinant of insulin resistance as assessed by HOMA-IR (ß = 0.093, p < 0.001), carotid thickness (ß = 0.086, p = 0.001) and pulse wave velocity (ß = 0.170, p < 0.001). CONCLUSION: Postprandial increase in BP is a novel risk marker for arteriosclerosis.

Quadriceps sarcopenia and visceral obesity are risk factors for postural instability in the middle-aged to elderly population.

AIM: Aging shifts body composition to comprising more fat and less muscle. Sarcopenia, particularly in the knee extensors, and obesity, particularly visceral obesity, either alone or in combination, may exacerbate age-related physical disability. We investigated the association between age-related quadriceps (Qc) sarcopenia and visceral obesity, as measured by cross-sectional area (CSA), on postural instability. METHODS: Mid-thigh muscle CSA and abdominal visceral and subcutaneous fat area at the level of the umbilicus were assessed from computed tomography (CT) images in 410 apparently healthy independent middle-aged to elderly subjects attending the medical check-up program in Ehime University Hospital. Static postural instability using a posturograph and one-leg standing time with eyes open were assessed. RESULTS: Both abdominal visceral fat area and Qc muscle CSA corrected by body weight (BW) were associated with static postural instability, in addition to age and sex, while BW-corrected Qc muscle CSA predicted a short one-leg standing time. The combination of Qc sarcopenia, defined as greater than 1 standard deviation below the mean of a young group (age <60 years), and visceral obesity, defined as a visceral fat area of more than 100 cm(2), were associated with static postural instability, while Qc sarcopenia was related to a higher prevalence of one-leg standing time of less than 30 s, irrespective of visceral obesity. CONCLUSION: Thigh Qc sarcopenia and visceral obesity are associated with postural instability in middle-aged to elderly subjects. These findings suggest that age-related, site-specific fat and muscle mass alterations are associated with functional impairment.

Abnormal nocturnal blood pressure profile is associated with mild cognitive impairment in the elderly: the J-SHIPP study.

Mild cognitive impairment (MCI), a syndrome characteristic of the transition phase between normal cognitive function and dementia, has been shown to carry the risk of progression to dementia. Dysregulation of blood pressure (BP) is thought to be an indicator of cerebrovascular damage, including cognitive impairment. Here, we investigated the possible association of circadian BP variation with MCI in community-dwelling persons exhibiting no definitive dementia. Our study enrolled 144 persons (68+/-7 years). Nocturnal BP profile was defined as dipper, with a 10-19% drop in nocturnal systolic BP; extreme dipper, >or=20% drop; non-dipper, 0-10% drop; and riser, any increase in nocturnal BP. MCI was assessed using the MCI screen, a cross-validated, staff-administered battery of tests. Subjects with MCI (n=38) were significantly older (74+/-6, 67+/-6 years, P<0.001) and had higher frequency of apolipoprotein E varepsilon4 allele (36.8, 18.9%, P=0.018). Although the ambulatory measured BP and the percent changes in nocturnal systolic BP (-10+/-12% and -12+/-8%, respectively; P=0.291) did not differ between MCI subjects and normal controls, frequency of MCI was significantly higher in the extreme dippers (32.0%), non-dippers (30.0%) and risers (50.0%) than in dippers (13.2%, P=0.018). Multiple logistic regression analysis identified a blunted nocturnal BP decline, non-dipping or increase in nocturnal BP and extreme drop in BP as potent determinants of MCI (odds ratio 3.062, P=0.039), after adjustment for possible confounding factors, including apolipoprotein E varepsilon4 genotype. Abnormal nocturnal BP profile was found to be a strong indicator of MCI in otherwise apparently healthy community-dwelling elderly persons.

Association of central systolic blood pressure with intracerebral small vessel disease in Japanese.

BACKGROUND: Recent studies have reported the association between advanced arterial stiffness and brain small vessel diseases (SVDs). Two possible hemodynamic mechanisms, increases in central blood pressure (BP) and pulsatile flow load to the brain, have been speculated to link arterial stiffness and SVD. The carotid flow augmentation index (AI) has been proposed as an index of pulsatile flow to the brain. We compared its association with brain SVD with that of central BP in a general population. METHODS: Subjects were 500 individuals free from symptomatic cardiovascular diseases with a mean age of 66.9 +/- 8.4 years. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Carotid flow AI was obtained by Doppler ultrasonography. The presence of silent cerebral lacunar infarcts (SCI) was determined as a manifestation of SVD by 3-tesla magnetic resonance imaging (MRI). Second peak radial systolic BP (SBP2) and pulse pressure (PP2) were used as estimates of central BP. RESULTS: baPWV was significantly associated with radial BP2 (r = 0.55, P < 0.0001) but not with carotid flow AI (r = 0.03, P = 0.51). Radial BPs and baPWV, but not flow AI, were significantly higher in subjects with SCI. Radial SBP2 had higher odds ratio for the presence of SCI than brachial SBP, PP, and radial PP2. Logistic regression analysis showed that radial SBP2, but not flow AI, was independently related to the presence of SCI. CONCLUSION: These findings indicate that the SBP2, an estimate of central SBP, is significantly associated with the presence of SVD in an apparently healthy general population.

Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men.

OBJECTIVE: Sarcopenia of legs is an important cause of physical dysfunctions, frailty and dependence. Many predisposing and underlying mechanisms of sarcopenia, including age, sedentary life style, oxidative stress, insulin resistance, and low testosterone levels, are also known to be related to atherosclerosis, which is another leading cause of morbidity and mortality in elderly subjects. In this study, we investigated our hypothesis that sarcopenia and atherosclerosis are associated with each other to facilitate mutual abnormalities. METHODS: Study was performed in apparently healthy 496 middle-aged to elderly persons recruited consecutively among the visitors to the medical check-up program, Anti-Aging Doc, in a University hospital, from March 2006 to December 2007. Mid-thigh muscle cross-sectional area (CSA) was measured by computed tomography and corrected by body weight (CSA/BW). Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured. RESULTS: Thigh muscle CSA/BW was significantly and negatively associated with carotid IMT and baPWV in men but not in women. After correction for other confounding parameters, baPWV was an independent risk for the presence of sarcopenia in men (odds ratio of 1 m/s increase of baPWV=1.14, 95% CI=1.01-1.30, p<0.05) in addition to age, body height, low physical activity, free testosterone level. Conversely, thigh muscle CSA/BW was an independent determinant of baPWV (beta=-0.15, p<0.01) in addition to age, blood pressure, triglyceride, and antihypertensive drug use in men. CONCLUSIONS: Arterial stiffness is related to thigh muscle volume in men. Sarcopenia and atherosclerosis may share a common pathway and interact with each other to facilitate mutual abnormalities.

Associations between short one-leg standing time and speed of sound of calcaneal bone in a general population: the Shimanami Health Promoting Program (J-SHIPP) study.

AIM: Loss of bone mass is a major cause of fracture in the elderly. One-leg standing (OLS) time has been postulated to be predictive of reduced bone mass. Here, we conducted a cross-sectional study to clarify whether OLS time measurements are associated with the speed of sound (SOS) of calcaneal bone independent of muscle mass in the lower extremity, a major confounding factor for the association, in a community-dwelling population of middle-aged to elderly subjects. METHODS: The study subjects consisted of 770 apparently healthy middle-aged to elderly community-residents. Quantitative assessment of calcaneal bone was done using a quantitative ultrasound technique. OLS time with eyes open was measured with a maximum time of 60 s. Femoral muscle cross-sectional area (CSA) was measured from a computed tomography image. RESULTS: Subjects who could not stand 60 s on one leg (n = 192) showed significantly lower SOS (1487 +/- 20, 1501 +/- 24 m/s, P < 0.001). In addition, femoral muscle CSA was positively associated with SOS (male, r = 0.148, P < 0.01; female, r = 0.204, P < 0.001). However, multiple regression analysis adjusted for age, sex and muscle CSA identified short OLS time less than 60 s as an independent determinant of SOS in both male (P < 0.001) and female (P < 0.05) subjects. OLS time was significantly associated with posturograph-measured mobility of the center of gravity. However, multiple regression analysis showed no significant correlation between balance impairment and SOS (P > 0.1). CONCLUSION: OLS time less than 60 s was significantly associated with reduced SOS independent of age, sex and muscle mass in the lower extremity.

Vaccine-associated paralytic poliomyelitis caused by contact infection.

We encountered an adult patient with acute anterior poliomyelitis (AAP), whose monoparesis developed 28 days after his son's immunization with oral poliovirus vaccine (OPV). Neurological and electrophysiological examinations suggested that his muscular wasting of the left lower limb was due to a lower motor neuron disorder, and magnetic resonance imaging revealed the responsible lesion in the left anterior horn at the thoracolumbar junction. His stool was found to include poliovirus type 3, mainly originating from Sabin 3 by neutrization antibody and PCR-restriction fragment length polymorphism method. This indicated that the AAP resulted from contact with his son. This patient raises the question about OPV in polio-free countries.