Brain atrophy during normal aging and its relation to chronic smoking was studied using quantitative volumetric measurements of computed tomography. Study was performed about 159 smokers and 194 non-smokers with no neurological abnormality nor focal abnormality in CT scans. Each pixel of head CT scans was computed and Brain Volume Index (BVI) was calculated. BVI showed a significant decrease in smokers compared to non-smokers in three age groups, 50-to-54, 55-to-59 (p<0.001, both) and 65-to-69 (p<0.05). A dose-response study in the male showed that BVI in smokers was significantly lower than that for non smokers. Mean BVI tended to decrease when the smoking index increased but the trend was not significant. The systolic blood pressure and serum triglycrides of smokers were significantly higher than non-smokers (p<0.002 and p<0.05). It was suggested that age-related brain atrophy was enhanced by chronic smoking. Previously we showed that cerebral blood flow (CBF) was significantly lower in smokers than in non-smokers. Then, we suggest the following hypothesis; smoking chronically advances atherosclerosis, both atherosclerosis and high blood pressure reduce CBF, reduced CBF accelerated the lose of neurons which finally renders the brain atrophic.

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Degree of disability of the elderly, especially direct causes of immobilization and complications were analyzed in institutionalized elderly. Subjects were a total of 540 cases (174 men and 366 women) with their ages ranging between 62 and 101 (mean of 82.8) years in Tokyo Metropolitan Itabashi Nursing Home. Underlying diseases were classified into those of nervous system (cerebrovascular disease, Parkinson syndrome etc), locomotor system (fracture of the neck of the femur, osteoarthritis etc), dementia and various other diseases. Degree of disability was classified by walking ability into 4 groups; grade 4 for immobilization, grade 3 for mobility around bed, grade 2 for using walker or wheelchair, grade 1 for walking (with or without cane). (1) Classification of disability: There were 182 cases (33.7%) of grade 4, 52 cases (9.6%) of grade 3, 169 cases (31.3%) of grade 2, and 137 cases (25.4%) of grade 1. (2) Disability and age: There were more than 40% of grade 4 disability in nonagenarians. (3) Disability and diseases: In 182 cases of grade 4, there were 289 neurological diseases (158.8%), 123 locomotor diseases (67.6%) and various other diseases (129.7%). The incidence of these disease groups was 101.9%, 69.2%, 126.9% in grade 3, 87%, 72.2%, 155% in grade 2, and 86.1%, 38.7%, 183.2% in grade 1, respectively. Incidence of neurological diseases was especially high in grade 4, and that of various diseases in grade 1. (4) Causes of immobilization: A total of 182 cases of immobilized elderly could be explained by neurological diseases in 51 (28%), locomotor diseases in 38 (20.9%), dementia in 11 (6%), combination of these 3 groups of diseases in 74 (40.7%) and others in 8 (4.4%). In other words, immobilization was induced by single disease in 79, and by plural diseases (including same and different organs) in 103 cases. In conclusion, the main causes of immobilization were neurological diseases, such as cerebrovascular diseases, and locomotor diseases, such as fracture of the neck of the femur. There were, however, many other causes, and mechanism was more complex by combination of diseases.

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In the previous reports, we described that hyponatremia in the elderly with unknown etiology could be devided into two subgroups according to urinary sodium concentration. The pathophysiological findings of the first subgroup of hyponatremia with urinary sodium concentration over 50mEq/l were compatible with those of SIADH, namely, dilutional hyponatremia except for the presence of mild renal dysfunction. The purpose of this study was to clarify the ADH secretion in this group. In the normal aged (n=5), serum osmolality and plasma ADH levels were decreased after water load, but plasma renin activity was not changed. The delta plasma ADH/delta serum osmolality were higher (0.50±0.19) than the values reported in the young subjects. This result suggests that the normal aged have a hypersensitivity for ADH secretion by serum osmolality. Plasma ADH levels in the aged hyponatremia (serum Na≤125mEq/l, urinary Na>50mEq/l), 6.6±1.8pg/ml, were significantly higher than those in controls (4.6±1.7pg/ml, p<0.02). Plasma ADH/PRA ratio showed no significant difference between the hyponatremia and the controls. However, plasma ADH/serum osmolality in the hyponatremia showed significantly higher value (2.68±0.82) than those in controls (1.57±0.59, p<0.01). According to the threshold theory, plasma-ADH/serum osmolality ratio indicates the sensitivity of the osmotic regulation in ADH secretion. Therefore, the higher plasma ADH/serum osmolality ratio in the aged dilutional hyponatremia suggests that the dysfunction in osmotic regulation play an important role in the pathogenesis of this morbid state. Furthermore, we have examined the effect of hypertonic saline with or without furosemide in the aged dilutional hyponatremia. Serum Na, serum osmolality and plasma ADH were increased by the treatment. Serious determination of plasma ADH, serum Na and osmolality in the course of the treatment, suggested that not only the sensitivity but also the set point of the regulating system in ADH secretion might be disturbed.

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An ageing phenomena in relation to metal elements (Zn, Cu and Fe) were investigated on a rabbit lens. For the studies, a new analytical method for metals, i.e., an atomic absorption spectrophotometry/high performance aqueous gel permeation chromatography (AA/HPAGPC) was used. It was first confirmed by the analyses of the metal behaviours on the ageing phenomenon that the metals were closely related to the ageing phenomenon. The ageing phenomenon was dependent on the correlationship in the quantity between the two metal elements, Zn and Cu in the lens, and the following new relationship was obtained to estimate the ageing phenomenon. Log (Zn/Cu)=logK+1/NlogY, Zn and Cu: Zn and Cu contents (μg/1.0g of the lens); logK and 1/N: ageing coefficients; Y: age (month). The molecular weight distributions of the metal-containing compounds contributing to the estimations of the ageing phenomenon were first obtained from the metal analyses with the rabbit lens by the AA/HPAGPC. The distribution patterns obtained suggested the following facts for the ageing phenomenon, i.e., there were both changes in the quantities and the qualities of the metal-containing compounds in the lens on the ageing phenomenon between the periods of the growth and the atrophy bordering the adult ages.

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Five autopsied brains from centenarians (100-105 years of age) were examined pathologically. The results were as follows: 1) All cases consisted of females, who had been healthy through their entire lives and belonged to the families of long lifespan. 2) The psychiatric disorder appeared first in the late of life. 3) Causes of death were pneumonia, heart failure, lung cancer, etc. 4) Visceral organs were severely atrophic. The brains weighed 950-1170g, with diffuse cortical atrophy. 5) Macroscopical lesions were observed in 3 cases, which consisted of small bleeding and softening. 6) Histologically, the changes of physiological aging, i.e. nerve cell loss, atrophy, lipofuscin accumulation, axonal dystrophy, Marinesco body, torpedo, were markedly observed. On the other hand, the changes of pathological aging, i.e. senile plaques, Alzheimer's neurofibrillary tangles, amyloid angiopathy, Lewy body, granulovacuolar degeneration, Hirano body, appeared inconsistently. Abundant senile plaques were observed in 2 cases and Alzheimer's neurofibrillary tangles in all cases. In conclusion, the centenarian brains are characterized in the changes of both physiological and pathological aging, and also in the presence of slight vascular changes.

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The serum TSH, T₃, T₄ and TBG values were measured in 313 elderly subjects with the age of 60 years or more who lived in the home for the healthy aged. The serum T₃ and TBG values showed a negative correlation (p<0.01, both) with the age, but the serum TSH and T₄ values did not. Consequently the normal renge was determined as, the mean±2SD of the TSH and T₄ values of the total subjects, and those of the T₃ and the TBG values of each decade (60, 70, 80 and 90). When compared with the reported data measured in the hospital samples, the present results (home samples) showed higher values in T₃, T₄ and TBG levels. According to the normal range determined, 69 (54%) of the 127 patients with non-thyroidal illness were noted to have low T₃ value. In the 69 low T₃ patients, normal serum T₄ values were noted in 62 (low T₃ group) and low T₄ values in 7 patients (low T₃ low T₄ group). The underlying diseases were not different between the two groups but hemoglobin, total serum protein and total cholesterol values were lower and the mortality was higher in the low T₃ low T₄ group when compared with the low T₃ group.

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The present study was undertaken to identify quantitatively the major factors predisposing elderly cardiac patients to digitalis toxicity. In 88 cardiac patients under maintenance therapy with digoxin in doses of 0.25mg daily, comparative studies were made not only of patients intoxicated with digitalis and non-intoxicated patients but also of elderly patients (sixty or more years) and young patients (below sixty years). Serum digoxin concentration was measured by radioimmunoassay. The data were analyzed by multivariate statistical analysis using 15 readily obtainable variables. (1) The intoxicated patients had a mean serum digoxin concentration of 3.06±1.34 (SD) ng/ml, while non-intoxicated patients had a mean of 0.96±0.55ng/ml (p<0.001). The range of overlap between the two groups extended from 1.7 to 2.6ng/ml. The patients with digoxin toxicity were significantly older and had diminished renal function, smaller body weight and larger cardiothoracic ratio compared with the non-intoxicated patients. (2) The mean serum digoxin concentration in the elderly patients was 1.60±1.21ng/ml which was significantly higher than that in the young group (p<0.001). The incidence of digitalis intoxication was significantly greater in the elderly patients (24.5%) than in the young group (6.4%) (p<0.05). The elderly patients had diminished renal function and smaller body weight compared with the young group. (3) The analysis of factors contributing to the elevation of serum digoxin concentration by means of multiple regression analysis revealed that renal function, as judged by serum creatinine levels, and body weight were important. These variables accounted for 32.67% and 9.33% of the total variance of the serum digoxin concentration, respectively. The increase in cardiothoracic ratio and coadministration of spironolactone had a smaller but significant effect on the elevation of serum digoxin concentration. Age itself was not a significant factor. All of the 15 variables together accounted for 54.2% of the total variance of the serum digoxin concentration. (4) Discriminant analysis of digitalis intoxication showed that major factors contributing to the development of toxicity are diminished renal function, severity of underlying heart disease as judged by cardiothoracic ratio, smaller body weight and hypokalemia. Again, age itself was not a significant factor. (5) Digoxin in doses of 0.25mg daily, which is almost always well tolerated by young patients, is too high to be tolerated by elderly patients. If any of the conditions such as diminished renal function, reduced body weight or deterioration in underlying heart disease are recognized, the maintenance dose of digoxin should be reduced from 0.25mg to 0.125mg daily in the elderly cardiac patients. If electrolyte imbalance, especially hypokalemia, occurs, it should be treated as soon as possible. Also, it is very important to determine the serum digoxin concentration frequently in the clinical course in order to detect digitalis intoxication early.

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Serum apolipoproteins and various other risk factors for atherosclerosis were analyzed by a multivalidation technique in normal subjects and patients with old myocardial infarction, angina pectoris and cerebral thrombosis in a steady state. By evaluation with discriminant equations derived respectively for discrimination of patients with the above diseases from normal subjects, the accuracies of the risk factors were found high in the following order. (1) Old myocardial infarction: apolipoprotein A-I/apolipoprotein B, apolipoprotein A-I+A-II/apolipoprotein B, apolipoprotein B, atherosclerotic index, LDL cholesterol, cholinesterase/HDL cholesterol, total cholesterol, triglycerides, apolipoprotein A-II, apolipoprotein A-I, HDL cholesterol, cholinesterase, apolipoprotein C-II, apolipoprotein C-III and apolipoprotein E. (2) angina pectoris: apolipoprotein A-I+A-II/apolipoprotein B, apolipoprotein A-I/apolipoprotein B, triglycerides, apolipoprotein A-I, apolipoprotein B, apolipoprotein C-II, total cholesterol, LDL cholesterol, atherosclerotic index, cholinesterase, HDL cholesterol, cholinesterase/HDL cholesterol, apolipoprotein C-III, apolipoprotein A-II and apolipoprotein E. (3) Cerebral thrombosis: apolipoprotein A-I+A-II/apolipoprotein B, apolipoprotein A-I/apolipoprotein B, apolipoprotein A-II, atherosclerotic index, apolipoprotein A-I, apolipoprotein C-II, HDL cholesterol, cholinesterase, triglycerides, cholinesterase/HDL cholesterol, apolipoprotein C-III, LDL cholesterol, apolipoprotein E, apolipoprotein B and total cholesterol. The above indicates that determination of serum apolipoproteins was very useful for discrimination of old myocardial infarction, angina pectoris and cerebral thrombosis from normal subjects and that determination of apolipoprotein B, total cholesterol and LDL cholesterol was useful for discrimination of old myocardial infarction but not for discrimination of cerebral thrombosis from normal subjects. These results suggested that serum lipids and apolipoproteins have different influences in various arteries, though they are the important risk factors for atherosclerosis and that the pathogenesis of atherosclerosis differs between cardiac and cerebral arteries.

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Effects of rehabilitation on disability due to cerebrovascular diseases in the aged were examined, and the prognostic indicators were analyzed. Subjects were a total of 150 patients (89 men and 61 women with their average age of 71 years), who were admitted to the Tokyo Metropolitan Geriatric Hospital for 1 year from April, 1983 to March, 1984, and received training by rehabilitation team. Among various activities of daily living (ADL), functional classification by walking ability was made; independent walking (with or without cane) as grade 1, locomotion within home grade 2, mobility around bed grade 3, and immobilized state as grade 4. Results: (1) There were 27 cases of cerebral bleeding and 123 of cerebral infarction. (2) Hospital stay for therapy were within 1 month in 29 cases, within 3 months in 69 and within 6 months in 52. (3) Distribution of initial functional status was 6 cases in grade 1, 25 in grade 2, 40 in grade 3 and 79 in grade 4; and that of final status was 40, 47, 36, and 27, respectively. There was an increase in cases of grade 1 and 2, and a decrease in grade 3 and 4. (4) Factors influencing final ADL (prognostic indicators) were enumerated as age, onset-admission-interval (O-A-I), decrease of intellectual faculties, poor motivation, hemineglect and cerebral infarction due to cortical branch occlusions. With aging, cases of recovery to grade 1 decreased, whereas cases remaining in grade 4 increased. As for the side of hemiparesis, 62 cases of left, 73 of right, 15 of bilateral hemiparesis showed no statistical difference on recovery. Sixty percent of those entering with an O-A-I of less than 6 months recovered to grade 1 or 2, compared to about 40% of those with longer O-A-I's. (5) The relationship of final functional status to discharge disposition showed that 101 cases (67.3%) were able to return home, whereas 49 cases (32.7%) remained in various institutions including hospitals and nursing homes. Discharge disposition of advanced disability tended to be institution, and a group of grade 4 returned home in only 33.3%. In conclusion of the effects of rehabilitation on cerebrovascular diseases, more than half (87/150) was recovered to grade 1 or 2 even in the aged, but 33% of cases could not return home due to variable unfavorable factors resulting in remaining disability.

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The undiagnosed cases of malignant lymphoma (ML) were eveluated with special reference to the clinical data. Seven of 38 cases of ML were undiagnosed clinically in the autopsy protocol of the Tokyo Metropolitan Geriatric Hospital from 1972 to 1983. Clinical data were available in 6 of 7 cases, which were compared with clinical data at admission of 20 cases of clinically diagnosed ML. Although swelling of superficial lymphnodes were observed in 33% of undiagnosed cases in contrast to 85% of diagnosed cases, laboratory data, such as lymphocytopenia, high titer of LDH in the serum, elevated erythrocyte sedimentation rate and positive CRP were more frequentry observed in undiagnosed cases. Autopsy revealed that 5 of 6 undiagnosed cases were thought to be extranodal in origin, and all cases were in stage IV. Extranodal and extended ML may comprise most of clinically undiagnosed ML of the elderly, but the routine laboratory data descrived above should be enough to arise suspicion of ML.

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