A comparison between volumetric data generated by voxel-based morphometry and manual parcellation of multimodal regions of the frontal lobe.

BACKGROUND AND PURPOSE: Volumetric measurements on structural MR images are an established method to investigate pathology-related volume changes in cortex. Manual volumetric methods have sometimes been referred to as the reference standard for quality control of automatic volumetric methods. While some automatic methods, like VBM, may rely on a template, manual methods use sulci as indirect landmarks for the subdivision of cortex. The purpose of this study was to compare volumetric data generated by MM and VBM on 4 multimodal regions in the frontal lobe. MATERIALS AND METHODS: We investigated 4 multimodal frontocortical regions by MM and VBM in patients with frontotemporal lobar degeneration and Alzheimer disease and controls. RESULTS: MM and VBM results were highly correlated for dorsolateral prefrontal cortex, orbitofrontal cortex, and hippocampus, but not for the dorsal and rostral anterior cingulate. VBM results were more consistent with results from previous studies on cingulate in frontotemporal lobar degeneration. Our results may potentially be explained by 2 factors. First, the volume of small cortical regions may be more affected by anatomic variability than large regions in the MM. Second, it has been shown that the location of multimodal cytoarchitectonic areas, such as the cingulate cortex, may be difficult to predict by the appearance of sulci and gyri. CONCLUSIONS: While both VBM and the MM may do equally poorly in predicting cytoarchitecture, the MM may add additional unrelated variance caused by anatomic variability. Thus, paradoxically, the higher anatomic precision of the MM may potentially cause a weaker relation to cytoarchitecture.

Putaminal volume in frontotemporal lobar degeneration and Alzheimer disease: differential volumes in dementia subtypes and controls.

BACKGROUND AND PURPOSE: Frontostriatal (including the putamen) circuit-mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not in Alzheimer disease (AD) or healthy aging. We sought to assess putaminal volume as a measure of the structural basis of relative frontostriatal dysfunction in these groups. MATERIALS AND METHODS: We measured putaminal volume in FTLD subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 25) and patients with AD (n = 18). Diagnoses were based on accepted clinical criteria. We conducted manual volume measurement of the putamen blinded to the diagnosis on T1 brain MR imaging by using a standardized protocol. RESULTS: Paired t tests (P < .05) showed that the left putaminal volume was significantly larger than the right in all groups combined. Multivariate analysis of covariance with a Bonferroni correction was used to assess statistical significance among the subject groups (AD, FTD, SD, PNFA, and controls) as independent variables and right/left putaminal volumes as dependent variables (covariates, age and intracranial volume; P < .05). The right putamen in FTD was significantly smaller than in AD and controls; whereas in SD, it was smaller compared with controls with a trend toward being smaller than in AD. There was also a trend toward the putamen in the PNFA being smaller than that in controls and in patients with AD. Across the groups, there was a positive partial correlation between putaminal volume and Mini-Mental State Examination (MMSE). CONCLUSIONS: Right putaminal volume was significantly smaller in FTD, the FTLD subtype with the greatest expected frontostriatal dysfunction; whereas in SD and PNFA, it showed a trend towards being smaller, consistent with expectation, compared to controls and AD; and in SD, compared with AD and controls. Putaminal volume weakly correlated with MMSE.

Cortical morphometric subclassification of frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a primary neurodegenerative disease comprising 3 clinical subtypes: frontotemporal dementia (FTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The subdivision is primarily based on the characteristic clinical symptoms displayed by each subtype. We hypothesized that these symptoms would be correlated to characteristic patterns of brain atrophy, which could be indentified and used for subclassification of subjects with FTLD. MATERIALS AND METHODS: Volumes of 9 cortical regions were manually parcellated and measured on both hemispheres on 27 controls, 12 patients with FTD, 9 patients with PNFA, and 13 patients with SD. The volumetric data were analyzed by traditional t tests and by a multivariate discriminant analysis (partial least squares discriminant analysis). RESULTS: The ensemble or pattern of atrophy was a good discriminator in pair-wise comparison between the subtypes: FTD compared with SD (sensitivity 100% [12/12], specificity 100% [13/13]); FTD compared with PNFA (sensitivity 92% [11/12], specificity 89% [8/9]); and SD compared with PNFA (sensitivity 86% [11/13], specificity 100% [9/9]). Temporal-versus-frontal atrophy was the most important pattern for discriminating SD from the other 2 subtypes. Right-sided versus left-sided atrophy was the most important pattern for discriminating between subjects with FTD and PNFA. CONCLUSIONS: FTLD subtypes generally display a characteristic pattern of atrophy, which may be considered in diagnosing patients with FTLD.

Caudate nucleus volumes in frontotemporal lobar degeneration: differential atrophy in subtypes.

BACKGROUND AND PURPOSE: Frontostriatal circuits involving the caudate nucleus have been implicated in frontotemporal lobar degeneration (FTLD). We assessed caudate nucleus volumetrics in FTLD and subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 27) and subjects with Alzheimer disease (AD, n = 19). MATERIALS AND METHODS: Diagnoses were based on accepted clinical criteria. Manual volume measurement of the head and body of the caudate, excluding the tail, was conducted on T1-weighted brain MR imaging scans, using a published protocol, by a single analyst blinded to the diagnosis. RESULTS: Paired t tests (P < .05) showed that the right caudate nucleus volume was significantly larger than the left in controls and PNFA. No hemispheric asymmetry was found in AD, FTD, and SD. Across the groups, there was a positive partial correlation between the left caudate nucleus volume and Mini-Mental State Examination (MMSE) scores (r = 0.393, n = 76, P = .001) with higher left caudate volumes associated with higher MMSE scores. Multivariate analysis of covariance was used to assess the statistical significance between the subject groups (AD, FTD, SD, PNFA, and controls) as independent variables and raw right/left caudate volumes at the within-subject level (covariates: age and intracranial volume; P < .05). Control volume was largest, followed by AD (93% of control volume), SD (92%), PNFA (79%), and FTD (75%). CONCLUSIONS: Volume of the head and body of the caudate nucleus differs in subtypes of FTLD, due to differential frontostriatal dysfunction in subtypes being reflected in structural change in the caudate, and is correlated with cognition.

Inverse association of serum cholesterol with plasma insulin in the elderly. Cross-sectional and prospective analyses.

Cross-sectional studies have suggested that high plasma insulin is associated with relatively low levels of low density lipoprotein (LDL)-cholesterol. The present study was aimed at re-testing this association in a 70-year-old age cohort (N = 1023), and testing whether it could be caused by excessive mortality of hyperinsulinemic subjects with high LDL-cholesterol. A reverse U-shaped association between LDL-cholesterol and fasting plasma insulin was confirmed. LDL-cholesterol, HDL-cholesterol and total cholesterol were lowest in the highest insulin quarter. These associations remained after adjustment for diabetes, obesity and general health status. The combination of high LDL-cholesterol (> 4.25 mmol/L, 75th percentile) and high insulin (> 10 IU/L, 50th percentile) was not associated with excess 5-year mortality in this age cohort. Nor was it associated with excess mortality in four other elderly age cohorts (N = 1188), in which similar associations of cholesterol and insulin have been demonstrated. Thus, the inverse association of LDL-cholesterol with fasting insulin in the elderly is not caused by selective over mortality.

Does the metabolic syndrome predict mobility impairment in the elderly?

The predictive importance of the metabolic syndrome and its components for declining mobility were tested in a 5-year follow-up study of four elderly birth cohorts (65, 75, 80 and 85 years of age; n=946). In the age group of 65 years, the subjects with mobility decline were more often diabetics (24.6 vs. 15.5%, P=0.060), had higher blood glucose (6.2 vs. 5.8 mmol/l, P<0.05), higher fasting plasma insulin (13.2 vs. 11.4 IU/l, P<0.01), and higher body mass index (28.4 vs. 27.2 kg/m(2), P<0.05) than the others. In the 75 year-old group, the mobility decline was associated with lower HDL-cholesterol (1.4 vs. 1.6 mmol/l, P<0.05) and higher insulin (15.9 vs. 12.8 IU/l, P<0.10). In the 80 year-old group, insulin was higher in subjects whose mobility declined (11.3 vs. 17.9 IU/l, P<0.05) but in the oldest group insulin tended to be lower in the subjects with declining mobility. In non-diabetic subjects, blood glucose and plasma insulin were associated with declining mobility in the 65 year-old cohort, only. After controlling for gender and baseline mobility, one quartile of both insulin and BMI increased the probability of mobility decline by 35%, mainly of difficulties in walking up stairs. Of the components of metabolic syndrome, obesity and hyperinsulinemia as its consequence appear causal of declining mobility.

Does fasting plasma insulin increase by age in the general elderly population?

The aim of this study was to examine the association of fasting plasma insulin with age. Insulin levels are influenced by obesity, physical inactivity, and medications, e.g., thiazide diuretics and beta adrenergic blockers. Further, comorbidity and pre-terminal conditions may confound the age-association of insulin. 1197 random subjects from four birth cohorts of the general aged population in southern Finland were examined, and followed for five years. Insulin levels at baseline tended to increase in men to the age of 75 years (mean 15.1 mU/L, SE 2.18), and in women to the age of 80 years (mean 15.9 mU/L, SE 1.14). The same association was seen among survivors in a five-year follow-up. These associations remained significant after controlling for obesity, physical inactivity and hyperinsulinogenic medications.

Impacts of components of the metabolic syndrome on health status and survival in an aged population.

The clinical significances of different components of the multiple metabolic syndrome were studied in a five-year follow-up study of random persons (n = 1,199) of four birth cohorts at ages 65, 75, 80, and 85 years. The subjects were examined clinically and their serum lipids, blood glucose, plasma insulin, blood pressure, and health score were determined. The health score was measured using a visual analogue scale. All subjects were followed for 5 years. Health score, diastolic blood pressure and body mass index declined over age, but serum triglycerides, and blood glucose were similar, whilst serum high density lipoprotein (HDL)-cholesterol increased. Among women fasting plasma insulin was lowest in the age group of 65 years. The associations of components of the multiple metabolic syndrome varied by age. In the age groups of 65 and 75 years high body mass index, plasma insulin, glucose, triglycerides and low HDL-cholesterol were associated with impaired health. In the age group of 85 years high blood pressure, total cholesterol, and HDL-cholesterol were associated with good health. The baseline health score was consistently lower in the decedents than survivors of all age groups, but components of the metabolic syndrome were generally not associated with impaired survival.

Elevated fasting plasma insulin in a general aged population: an innocent companion of cardiovascular diseases.

OBJECTIVE: Although high insulin levels have been linked to cardiovascular disease, the role of insulin as an independent risk factor has been questioned. Our objective was to examine the association of fasting plasma insulin with cardiovascular disease as well as to investigate the prognostic value of insulin with respect to survival. DESIGN: A 5-year follow-up of random samples from four birth cohorts age 65 (n = 660), 75 (n = 194), 80 (n = 179), and 85 (n = 162) years at baseline. SETTING: Two urban communities in southern Finland. MEASUREMENTS: Clinical and laboratory investigation at base line with collection of date and cause of death information during follow-up. RESULTS: Subjects with cardiovascular disease generally had higher levels of fasting plasma insulin than did subjects without cardiovascular disease (13.9 mU/L vs 11.2 mU/L, P < .001). Heart failure and hypertension were associated with significant 30 to 80% elevations of insulin levels in all but the oldest group. In the 65-year-old group, all vascular diseases were associated with significantly elevated insulin. The associations were generally not explained by body mass index or by use of diuretics or beta-blockers. During the follow-up insulin was generally not associated with an impaired survival. On the contrary, in subjects with manifest cardiovascular disease, high insulin was associated with a rather favorable 5-year survival prognosis. Exclusion of subjects who died during the first 500 days of follow-up did not change these associations. CONCLUSION: Albeit fasting plasma insulin appeared to be secondarily associated with cardiovascular disease in this general aged population, it was related to a fair or favorable survival prognosis.

High plasma insulin is associated with lower LDL cholesterol in elderly individuals.

To investigate possible relationships between plasma low density lipoprotein (LDL) cholesterol and fasting plasma insulin in the elderly, cross-sectional random samples of age cohorts (65, 75, 80 and 85 years, n = 1188, M/F 38/62 percent) were studied in the neighbouring cities of Helsinki and Vantaa, Finland. Plasma total and high density lipoprotein (HDL) cholesterol, plasma triglycerides, blood glucose and plasma insulin were measured after an overnight fast. LDL cholesterol was calculated using the Friedewald equation. Statistical analyses were performed separately in subjects with non-insulin-dependent diabetes mellitus (NIDDM, n = 219) and non-diabetic subjects (n = 969). Comparison of lipid levels by insulin quartile (I < 7.4 IU/1, II 7.4-10.0, III 10.1-15.0, IV > 15.0) showed that total and LDL cholesterol decreased in the highest insulin quartile (P = 0.003). This trend prevailed after adjustments for age, gender, body mass index, blood glucose and serum triglycerides, and it was significant also in normotriglyceridemic (serum triglycerides <2.3 mmol/l) subjects. Furthermore, the association between high insulin and lower cholesterol was seen in normoglycemic (fasting blood glucose <6.7 mmol/l) and diabetic subjects. Lower LDL cholesterol in elderly subjects with higher fasting insulin may reflect poor health or a 'harvesting' effect, but the results may also be due to effects of insulin on LDL catabolism and/or cholesterol absorption.

The impact of 25 years of iodine prophylaxis on the adult thyroid weight in Finland.

The effect of iodine prophylaxis on endemic goiter was studied in an adult Finnish population by comparing autopsy records from 1959 and 1984. In the 1950's the iodine intake calculated both from urinary excretion of stable iodine and from food analysis data was 50-70 micrograms per day the intake being lower in the main endemic area in the eastern part of the country. The use of iodized salt raised these figures only by 15 micrograms per day. At the beginning of the 1980's the iodine intake calculated in the same way was around 300 micrograms per day all over the country. Initially 696 records from 1959 and 525 from 1984 were analyzed. Excluded were cases with primary or secondary malignant thyroid tumors, autopsies with incompletely recorded thyroid weight, and autopsies from patients submitted to pituitary or thyroid surgery or radiation therapy. Finally, 318 cases from 1959 and 478 from 1984 were accepted. A significant decrease in thyroid weight from a mean of 44 to a mean of 34 g was observed. The difference between the two populations was most marked in the age groups below 45 yr. In these age groups the mean thyroid weight was about 20-27 g which can be regarded as normal. In the age groups over 75 years there were no significant differences. These data indicate that the iodine prophylaxis gradually eradicates the endemic goiter in Finland but that it requires still some 25-35 yr before it has disappeared also in the oldest age groups.

Norepinephrine-stimulated fatty-acid release and oxygen consumption in isolated hamster brown-fat cells. Influence of buffers, albumin, insulin and mitochondrial inhibitors.

Brown fat cells isolated from adult golden hamsters have earlier been found to respond to addition of the physiological agonist norepinephrine with an increased rate of oxygen consumption and with fatty acid release. Working with these cells, we found the following. 1. The presence of albumin in the incubation medium (phosphate buffer) increases norepinephrine-induced fatty acid release and tends to stabilize the rate of oxygen consumption; bubbling of phosphate buffer with 5% CO2 in air has only a slight effect on fatty acid release. 2. In the presence of albumin, the norepinephrine-induced rate of oxygen consumption is also stable in bicarbonate buffer; it is higher than in the phosphate + CO2 buffer and the brown fat cells have a higher sensitivity to norepinephrine. 3. 20 mM phosphate (as e.g. present in a phosphate buffer) inhibits both fatty acid release and oxygen consumption. 4. Insulin inhibits the rate of oxygen consumption, but only at suboptimal concentrations of norepinephrine. 5. Atractylate inhibits submaximal norepinephrine-induced respiration, indicating that some oxidative phosphorylation takes place in norepinephrine-stimulated brown fat cells. 6. Fatty acid export from brown fat should be regarded as physiologically important.

Studies on norepinephrine-induced efflux of free fatty acid from hamster brown-adipose-tissue cells.

Cells were isolated from brown adipose tissue of warm-adapted hamsters and the fate of free fatty acids released during norepinephrine-induced lipolysis was investigated. The isolated resting cells contain between 100-400 nmoles cell-associated free fatty acids per 10(6) cells; most preparations contained about 200 nmoles/10(6) cells. During norepinephrine-stimulated lipolysis, the level of cell-associated free fatty acids remains constant or decreases gradually, but does not increase, while the concentration of extracellular fatty acids increases linearly. The rate of norepinephrine-stimulated efflux of free fatty acids was 40 +/- 20 nmol X min-1 X 10(6) cells-1 (n = 11) at 37 degrees C. The data strongly indicate that brown adipose tissue can supply free fatty acids to the circulatory system in hamster.

Gylcerol-3-phosphate shuttle and its function in intermediary metabolism of hamster brown-adipose tissue.

1. Brown adipose tissue of the hamster possesses high specific activities of soluble, cytoplasmic NAD-linked, as well as mitochondrial flavin-coupled, glycerol-3-phosphate dehydrogenases. The ratio of the two enzyme activities is high (close to 1), when compared with other tissues of the hamster. 2. In the presence of rotenone, NADH is oxidised very poorly by homogenates of brown adipose tissue. A high rate of oxidation is obtained upon further addition of dihydroxyacetone phosphate, which itself is negligible oxidised. When followed fluorimetrically glycerol 3-phosphate can also be observed to induce NADH oxidation, but only after a significant lag time. Similar results are obtained with isolated mitochondria plus high-speed supernatant. With high-speed supernatant alone, only dihydroxyacetone phosphate has any effect, whereas with isolated mitochondria neither dihydroxyacetone phosphate nor glycerol 3-phosphate induce any NADH disappearance. 3. Respiration induced by NADH plus dihydroxyacetone phosphate in homogenates equals 56% of the respiration induced by glycerol 3-phosphate alone. 4. Respiration induced by NADH plus dihydroxyacetone phosphate, as well as that induced by glycerol 3-phosphate, is inhibited by the same concentrations of inhibitors as are required for inhibition of the mitochondrial dehydrogenase i.e. EDTA, long-chain unsaturated fatty acids, long-chain fatty acyl CoA esters. 5. In isolated brown adipocytes in the presence of rotenone, norepinephrine significantly inhibits respiration induced by glycerol 3-phosphate. 6. The results obtained are discussed with respect to the role of glycerol 3-phosphate as an electron sink for cytosolic reducing equivalents to maintain a low level of extramitochondrial NADH. A means of maintaining a level of glycerol 3-phosphate adequate for triglyceride synthesis is also considered.