Presence of circulating suppressive factor for muscarinic acetylcholine receptor in senile dementia

Alzheimer's disease is one of the main causes of senile dementia. Although its pathogenesis is not clear, some evidence has revealed that the activity of acetylcholine receptor in the brains of these patients is decreased. In the present study, possible circulating factors, affecting the muscarinic acetylcholine receptor of the synaptic vesicle from the rat brain, were evaluated in the serum of 95 senile subjects (34 males and 61 females, mean +/- SD age of 77.5 +/- 8.6 years). The cognitive function of these subjects was assessed by their Mini-Mental State scores, and they subjects were divided into non-dementic-subjects with a score of 21 or more, or subjects with dementia with a score of 20 or less. The latter were further divided into senile dementia with Alzheimer type (SDAT) and vascular type dementia (VS) using Hatchinski's ischemic score. The mean suppression rate by the serum from the SDAT patients on the binding of tritiated quinuclidinyl benzilate (3H-QNB), an antagonist for muscarinic acetylcholine receptor, to the rat synaptic membrane, was 18.1 +/- 7.2% of the control value, which was significantly greater than that of the non-dementic subjects, (4.7 +/- 3.8%). However, that in the VD group (8.4 +/- 6.8%), was not significantly different from the control value. Moreover the suppression rate of the serum on 3H-QNB binding showed significant positive correlated with score for the Mini-Mental State (r = 0.480, p less than 0.01) in the SDAT group. These data support the hypothesis that circulating suppression factors may participate in the pathogenesis of SDAT.     

Serum lipids, lipoproteins and apolipoproteins in patients with senile dementia]

Serum lipid, lipoprotein, apolipoprotein, and sterol profiles were studied in 22 patients with senile dementia of the Alzheimer type (SDAT) and 29 patients with vascular dementia (VD). Levels of high density lipoprotein-cholesterol (HDL-C) were lower in both patients groups of SDAT and VD than in control group. Apolipoprotein AI and AII are two major proteins in HDL. In this study, apolipoprotein AI levels were normal, but apolipoprotein AII levels were lower in the patient groups, especially in the VD group, than in the control group. Lipoprotein(a) levels were higher in both patient groups, especially in the VD group. There were no differences of cholesterol, cholesterol precursors (desmosterol and lathosterol), and plant sterols (campesterol and beta-sitosterol) among the three groups. Murine apolipoprotein AII is a serum precursor of murine senile amyloid protein, and the apolipoprotein AII variant with proline-->glutamine substitution at position 5 in the serum of accelerated senescence-prone mice is identical to the murine senile amyloid fibril protein from amyloid-deposited tissues of these mice. In human SDAT and VD, the reason for the low level of apolipoprotein AII remains unclear.     

A follow-up study on the outcome and relevant factors in senile dementia of Alzheimer type and vascular dementia]

We followed 126 patients with senile dementia of Alzheimer type (SDAT), and 129 over age 65 with vascular dementia (VD) who were diagnosed at the Center for Elderly Dementia in our institution between February 1990 and February 1993. At 5-year follow-up, 62 patients with SDAT and 71 patients with VD had died. These patients were assessed prospectively to investigate the neuropsychiatric and somatic factors related to the prognosis of SDAT and VD. There were no significant differences in the average age at onset and time of diagnosis of dementia between the SDAT and VD groups. Mean age at death, mean duration of dementia and 75% survival duration from dementia onset were shorter in patients with VD than in those with SDAT. Pneumonia was the most common cause of death in patients with either SDAT or VD, followed by geromarasmus in the SDAT group, and cerebrovascular and cardiovascular diseases in the VD group. In patients with SDAT, a poor prognosis was correlated with severe dementia, impaired intellectual function and degree of cortical atrophy. In patients with VD, physical complications, impaired motor function and hypoproteinemia enhanced the probability of death. This study confirmed that a progressive neurodegenerative course and physical conditions such as motor dysfunction or malnutrition are closely associated with the prognosis of patients with SDAT and VD, respectively.     

Senile dementia of the Alzheimer's type: an important risk factor for serious falls

In a longitudinal study of senile dementia and healthy aging, the occurrence of serious falls was examined in participants with senile dementia of the Alzheimer's type (SDAT) (n = 44) and in cognitively healthy elderly control participants (n = 56) over a 4-year period. Falls occurred in 36% of SDAT individuals versus 11% of controls. The higher frequency of falls in demented participants was not explained by greater neurologic deficit nor by increased drug use compared with controls. However, males with SDAT who reported falls, had higher mean blood pressures and were more likely to be medicated than males with SDAT who did not fall. These differences were not observed in women. Falls in SDAT participants were associated with an increased rate of institutionalization. SDAT is an important risk factor for serious falls, and falls are associated with loss of independence in demented patients.     

Age-related changes in both circadian and seasonal rhythms of rectal temperature with special reference to senile dementia of Alzheimer type

The biological rhythms of rectal temperature were documented in young (circadian variations) and elderly (circadian and seasonal variations) human subjects either in apparent good health or suffering from senile dementia of Alzheimer type (SDAT). All the subjects were synchronized. Data obtained showed a decrease of the body core temperature rhythm amplitude in the healthy elderly for each documented season but not in patients with SDAT. Seasonal variations in these rhythms were observed in these elderly groups of persons.     

Evaluation of animal-assisted therapy for the elderly with senile dementia in a day care program

We conducted animal-assisted therapy (AAT) for the elderly with senile dementia in a day care center. AAT was performed between July 27 and October 12, 1999 for a total of six biweekly sessions. The AAT group consisted of 7 subjects; 5 with senile dementia of Alzheimer's type (SDAT) and 2 with vascular dementia (VD). The control group was 20 elderly subjects (7 SDAT, 13 VD). The results were as follows: Comparing between MMS scores at the baseline and those three months later, the average score on MMS before AAT (baseline) was 11.43 (+/- 9.00), and that three months later was 12.29 (+/- 9.69). In the AAT group, the average baseline N-ADL score was 28.43 (+/- 14.00) and that after ATT was 29.57 (+/- 14.47). In the AAT group, the average baseline score on Behave-AD was 11.14 (+/- 4.85), and that three months after AAT was 7.29 (+/- 7.11) (p < 0.05). In the control group, the average baseline score was 5.45 (+/- 3.27) and that three month later was 5.63 (+/- 3.59). However, the results of eight subscales of communication behavior three months later were significantly low comparing to those at the baseline in the control group. The evaluation of CgA, which was a mental stress index, showed a decreasing tendency in the AAT group. Our findings suggested we should use several evaluation methods for evaluation of the changes of patients receiving AAT.     

Different regulation of adrenocorticotropin and cortisol secretion in young, mentally healthy elderly and patients with senile dementia of Alzheimer's type.

Previous studies suggest that an alteration of the neuroendocrine system may particularly occur in senile dementia of Alzheimer's type (SDAT). In the present study the reactivity of the hypophyseal-adrenocortical axis (HPA) in the elderly was assessed by hormonal stimulation of the hypophysis. Twelve young men (aged 21-24 yr), 15 mentally healthy elderly (aged 65-90 yr), and 12 patients with SDAT (aged 60-84 yr) received an iv bolus injection containing 50 micrograms CRH and 0.5 IU lysine vasopressin after a baseline period of 2 h. ACTH, cortisol, and dehydroepiandrosterone secretion was monitored over a period of 2 h before and after the injection. The baseline ACTH concentrations were increased in both groups of elderly, the baseline cortisol levels were not different in either group. The peak ACTH and cortisol levels were significantly elevated in the mentally healthy elderly, whereas senile demented patients showed a rise comparable with that in the young subjects. Moreover, in the demented patients the post-stimulus decline in plasma ACTH levels seemed to be delayed. Dehydroepiandrosterone was significantly lowered in subjects of all ages. Our results demonstrate an enhanced reactivity of the HPA in mentally healthy elderly. This is possibly due to a diminished sensitivity of the feedback regulation to glucocorticoids. However, SDAT patients had, compared to healthy elderly subjects, an attenuated response to CRH/lysine vasopressin and a prolonged ACTH secretion, indicating alterations of the HPA in this disease.     

Changes in Blood Glucose and Insulin Secretion in Patients with Senile Dementia of Alzheimer Type

ABSTRACT A retrospective study of 839 hospital records with various dementia diagnoses showed that 63 cases had a diagnosis of diabetes mellitus as well. None of these were found in the group of patients with senile dementia of Alzheimer type (SDAT). Oral glucose tolerance tests (OGTT) were performed in patients with SDAT, multiinfarct dementia (MID), cerebrovascular disease (CVD), hospitalized control patients (C_hosp) and healthy elderly persons (C_eld). Fasting blood sugar was significantly lower and the areas under the OGTT curves were significantly smaller in the SDAT group than in the CVD and the C_hosp group. SDAT patients had higher insulin levels than C_eld during the OGTT and on a statistically significant level 90 min after ingestion of sugar. Our findings suggest that SDAT and diabetes mellitus may not co-exist and that patients with SDAT have decreased blood sugar concentrations and elevated serum insulin levels. It is discussed whether this is an effect of the transmitter deficiencies in SDAT or may serve to explain these deficiencies.     

晚期糖基化终产物及其受体在白细胞中表达与老年人精神障碍的关系

目的 探讨血液中晚期糖基化终产物(AGEs)及其受体(RAGE)表达水平与老年人精神障碍性疾病的关系. 方法 将观察对象分为健康对照组31例、阿尔茨海默病(AD)组36例、血管性痴呆组20例、脑血管病所致精神障碍组28例.以荧光分光光度法测定各组血清AGEs水平,以逆转录多聚酶链式反应测定RAGE mRNA水平. 结果 血清AGEs水平在AD组、血管性痴呆组和精神障碍组分别为(477.1±36.2)AU/ml、(512.6±33.2)AU/ml和(415.25±32.5)AU/ml,均明显高于健康对照组(357.4±28.2)AU/ml(F=3.77,P<0.05).RAGE mRNA水平(RAGE/b-actin)分别为1.12±0.34、1.27±0.41和1.18±0.42,亦高于健康对照组的0.92±0.37(F=4.07,P<0.01),但各疾病组间差异无统计学意义(F=0.979,P>0.05).白细胞中RAGE mRNA水平与血清AGEs呈正相关关系(r=0.442,P<0.01). 结论 AD、血管性痴呆、脑血管病所致精神障碍患者血中的AGEs及其受体RAGE mRNA水平均较同龄健康老年人明显升高,AGEs与RAGE的相互作用可能直接或间接参与了老年人精神障碍性疾病的病理变化.     

A visual recognition memory test for the assessment of cognitive function in aging and dementia

Young, non-demented elderly, and elderly demented subjects were administered a computerized visual recognition memory task. In the task, subjects were instructed to point out the new object from a group of objects whose number was progressively incremented. The test was subject-paced and made use of face-valid stimulus materials; it is closely comparable to tests developed for memory assessment in non-human primates that are sensitive to the effects of hippocampal ablation. The present task was found to elicit significant differences in performance between young and non-demented aged subjects, between the non-demented and demented elderly, and between demented subjects in the early and more advanced stages of senile dementia of the Alzheimer type (SDAT). In a discriminant analysis, the visual recognition memory test scores correctly classified 72.6% of the aged subjects and early SDAT patients. No significant difference in task performance was found between SDAT patients and demented patients with a significant cerebrovascular etiological component. Thus, although the task does not appear to be suitable for diagnostic purposes it would be useful for the assessment of treatment effects upon age-related cognitive dysfunction.     

NMR imaging in dementia states. A diagnostic and quantitative study

Spin lattic relaxation times (T1) and proton density derived from proton nuclear magnetic resonance imaging data are measured in elderly patients with senile dementia of Alzheimer type (SDAT) and multi infarct dementia (MID) and the results compared with elderly controls. T1 values of the cerebral white matter are increased in the dementia groups and there is a statistical correlation with severity. Patients with SDAT have significantly differing proton density measures in cerebral white matter from those with MID. The potential value of these results are discussed together with the possible application to identify regional areas of damage.     

Clinical and epidemiological studies on inpatients with dementia

We have studied 97 patients with dementia who have been discharged from our hospital and 106 inpatients with dementia who have been admitted during last two years in our hospital. The diagnosis of dementia was done according to the criteria of DSM-III. Based on their clinical course, neurological signs, Hachinski's ischemic score and neuroradiological findings, we divided patients into 4 groups, [senile dementia of the Alzheimer type (SDAT), vascular dementia (VD), unclassified dementia and other dementias which includes dementia with Parkinson's disease or motor neuron disease, etc.]. Concerning 70 demented patients who died during hospitalization, the average age of onset and the duration of illness of SDAT were 80.5 years old and 4.6 years respectively and those of VD were 77.6 years old and 2.7 years respectively. The common causes of death were pneumonia (50%) and cardiac failure (24%). Recurrence of cerebral vascular accident (CVA) was also another frequent cause of death in VD. The most common behavioral problems causing admission in patients of SDAT were aimless wandering, nocturnal delirium, illusion and hallucination. In VD, nocturnal delirium, aimless wandering, violence and abnormal monologue were most common causes of admission. The important causes degrading ADL of inpatients were fracture, especially fracture of the hip joint, pneumonia, intestinal bleeding and CVA. Concerning the increase of the population of over 75 years old, it will be suggested that the care and treatment of demented patients in this age group will become a major social problem.     

Follow-up study on subjective quality of life for elderly persons with dementia using the Japanese version of Dementia Quality of Life Instrument (JDQoL)

PURPOSE: There are few longitudinal studies on the subjective quality of life for elderly persons living in their own homes. The purpose of this study was to clarify the validity and reliability of the Japanese version of the Dementia Quality of Life Scale (JDQoL) used in a follow-up survey as part of a longitudinal study in Japan. METHODS: A baseline study was conducted from November 2002 to January 2003, and a year later a follow-up study was conducted from October 2003 to January 2004. The subjects included 72 (19 men and 53 women) elderly persons with dementia living in their own homes. Sixty-six were diagnosed with vascular dementia (VD) and 6 had senile dementia of Alzheimer's type (SDAT). The follow-up study included 60 subjects (VD: 56 and SDAT: 4); _10 of the original subjects were hospitalized, one died, and one was unable to attend daycare because of deterioration. Evaluation was conducted using the JDQoL, MiniMental State Examination (MMSE), and Geriatric Depression Scale (GDS). RESULTS: For the MMSE, the average score of the subjects in the follow-up study was 20.87 (+/- 4.80), which was significantly higher than the score of subjects that were excluded from the follow-up study (17.82 +/- 5.65). At baseline, reliability coefficient was demonstrated by Cronbach's alpha value of 0.744 approximately 0.886. One year later, Cronbach's alpha was 0.723 approximately 0.872. Among the subjects in the follow-up study, MMSE scores decreased significantly compared with the baseline study. In the subscales of the JDQoL, Negative Feelings (reversal item) significantly improved and Feeling of Belonging significantly decreased after one year (p<0.05). Each subscale of the JDQoL had significant correlation with the GDS at baseline and follow-up. Scores on the GDS at baseline had significant correlation with Self Esteem, Positive Feelings, Negative Feelings, and Feeling of Belonging of the JDQoL at follow-up (0.320 to 0.504; p<0.05). CONCLUSION: We demonstrated that the reliability and validity of the JDQoL was comparable to the English version of DQoL. Subjective QOL did not decline for all sub-scales, Negative Feelings in the JDQoL significantly improved compared to baseline.     

A clinical study in elderly patients with Parkinson's disease using MRI and SPECT--Parkinson's disease and the lacunar state]

Parkinson's disease (PD) is often associated with dementia in elderly patients, and sometimes PD coexists with senile dementia of the Alzheimer type (SDAT) or cerebrovascular disease (CVD) in the elderly. However, since there are few previous clinical studies on the coincidence of, or relationship between PD and CVD, the authors evaluated these aspects in 34 elderly patients with PD using MRI and SPECT. All the patients were over 70 years old. The diagnosis of PD was based on the presence of three symptoms (resting tremor, cogwheel rigidity and bradikinesia) which are characteristic of PD, and the effectiveness of L-DOPA therapy. We therefore believe that patients with vascular Parkinsonism were excluded from our study. In 34 cases, 24 (71%) had MRI evidence of CVD (mainly the lacunar state). In the 10 cases who had no CVD, 2 (20%) had severe dementia and the decrease of regional cerebral blood flow (rCBF) in the temporal and parietal lobes bilaterally correlated with the SPECT findings commonly found in SDAT. A comparison of the rCBF and the results of Hasegawa's dementia score (HDS) (verbal intelligence score) was made between the patients with PD associated with CVD and the patients with PD who had no CVD and no SPECT findings which correlated with SDAT. The rCBF in the frontal lobes and the results of the HDS of the former group were significantly lower than those of the latter. As mentioned above, elderly patients with PD often had CVD, leading to dementia.(ABSTRACT TRUNCATED AT 250 WORDS)     

GHRH-induced GH response in patients with senile dementia of the Alzheimer type

To clarify the functional state of the somatotropinergic system at the hypothalamo-hypophyseal level in senile dementia of the Alzheimer type, the GHRH test was performed in three groups of subjects: a) healthy elderly subjects; b) early onset senile dementia patients; and c) late onset senile dementia patients. Intravenous administration of GHRH(1-44)NH2 (100 micrograms) elicited a marked plasma GH response with a maximum peak (709.54 +/- 259.0 pmol/l; P less than 0.005) 60 min after injection in patients with early onset senile dementia, but no significant response was detected in the other two groups. Electroencephalographic recording showed that GHRH modifies brain bioelectrical activity, decreasing frequency (0.52 +/- 0.15 Hz) and increasing amplitude (8.25 +/- 4.5 microV) of the electroencephalogram basic rhythm. The evaluation of mental performance and behaviour with a battery of different tests for mental assessment revealed that GHRH induces transient clinical changes in psychomotor behaviour. According to these results, it seems likely that the somatostatin deficiency reported in senile dementia of the Alzheimer type may account for the enhanced GHRH-induced GH response observed in patients with early onset senile dementia. In consequence, the GHRH test might constitute a useful antemortem marker for senile dementia of the Alzheimer type if the present results can be replicated in early stages of the disease.     

Lipid peroxidation and free radical scavengers in Alzheimer's disease

Lipid peroxidation products and defenses against free radical damage were determined in serum of 55 patients with senile dementia of the Alzheimer type (SDAT) and compared with values in 24 age-matched healthy control subjects. The following parameters were evaluated: lipid-conjugated dienes and trienes, malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in erythrocytes, vitamins E, C and A, zinc, selenium and copper, ceruloplasmin, transferrin and albumin. The results showed a statistically significant decrease in the levels of GSH-Px, vitamins E, C and A, zinc, transferrin and albumin in the SDAT group. On the other hand, most of the deficiencies concern the malnourished subgroup of the SDAT population (SOD, GSH-Px, vitamins E and C, selenium, zinc, transferrin and albumin). Such an alteration of free radical scavengers in the malnourished subgroup of the SDAT population could combine the radical and nutritional hypothesis advanced by some authors.     

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na(+)-dependent glutamate uptake sites and glutamate receptor subtypes--kainate, quisqualate, and N-methyl-D-aspartate--were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. Binding of D-[3H]aspartate to Na(+)-dependent uptake sites was reduced by approximately 40% throughout SDAT frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]Kainate receptor binding was significantly increased by approximately 70% in deep layers of SDAT frontal cortex compared with controls, whereas this binding was unaltered in superficial laminae. There was a positive correlation (r = 0.914) between kainate binding and senile plaque number in deep cortical layers. Quisqualate receptors, as assessed by 2-amino-3-hydroxy-5-[3H]methylisoxazole-4-propionic acid binding, were unaltered in SDAT frontal cortex compared with controls. There was a small reduction (25%) in N-methyl-D-aspartate-sensitive [3H]glutamate binding only in superficial cortical layers of SDAT brains relative to control subjects. [3H]Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others.     

Milacemide: a placebo-controlled study in senile dementia of the Alzheimer type.

OBJECTIVE: Milacemide, a MAO-B inhibitor that is also a prodrug for glycine, was tested as a treatment for senile dementia of the Alzheimer type (SDAT) because of its potential for enhancing cognition in animal models of impaired learning and memory. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Sixteen study sites, both university-affiliated and private. PATIENTS: A total of 228 outpatients (116 men and 112 women) with SDAT, ranging in age from 49-93 years. INTERVENTION: 1200 mg/day milacemide treatment for 1 month (113 patients received milacemide, and 115 patients received placebo). MAIN OUTCOME MEASURES: Alzheimer's Disease Assessment Scale and the Mini-Mental State Examination. RESULTS: Milacemide-treated SDAT patients did not show significant improvement in any of the outcome measures used. Significant elevations in liver enzymes in four subjects were of sufficient magnitude to necessitate withdrawal from the study. CONCLUSIONS: Milacemide does not appear to be an effective treatment in enhancing cognition in SDAT patients.     

Orthostatic hypotension in Alzheimer's disease: result or cause of brain dysfunction?

In Alzheimer's disease (AD), an association was found between autonomic dysfunction and frontal hypoperfusion in brain during orthostatic testing. To ascertain whether frontal hypoperfusion is dependent on longitudinal effects of hemodynamic disturbances, or contributes to them, we studied the relationship between the presence of orthostatic hypotension (OH) and resting cerebral blood flow (CBF) in late stages of AD. Twelve women with senile dementia of Alzheimer type (SDAT), and 15 non-demented women (mean age 82.6 years, SD 3.8 vs 81.8 years, SD 3.5) were examined with the orthostatic test. Four of 12 patients with SDAT, and 9 controls had OH (defined as systolic blood pressure fall > or = 20 mmHg). CBF was determined under resting conditions using 600 Mbq 99mTc HMPAO single photon emission computerized tomography (SPECT), and quantified in cortical areas in relation to cerebellum. In patients with SDAT and OH, CBF was lower in frontal and parieto-frontal cortical areas than in SDAT patients without OH. The former group was younger and had a shorter dementia duration. No significant differences in CBF were observed between controls with vs without OH. No differences in SDAT patients with or without OH were observed in the Berger dementia scale or Katz' ADL index. No difference in incidence of symptoms related to autonomic disturbances (diarrhea, obstipation, dysphagia, vertigo) was observed in either the SDAT or control group with regard to OH presence. We conclude that during the course of AD, OH can contribute to frontal brain changes and may exacerbate the disease. The further involvement of frontal dysfunction in aggravating blood pressure dysregulation in the elderly is discussed.     

Effects of aging on cerebral blood flow in dementia

Regional cerebral blood flow values were measured utilizing the 133Xe inhalation method in patients with multi-infarct dementia (MID) (n = 22, age 67.4 +/- 9.8 years), in patients with senile dementia of Alzheimer type (SDAT) (n = 36, age 63.8 +/- 8.0) and in age-matched normal healthy volunteers (n = 50, age 67.5 +/- 9.3). Mean hemispheric gray matter flow values were significantly reduced in MID (P less than 0.01) and SDAT (P less than 0.01) patients compared with age-matched normal volunteers. In normal volunteers, mean flow values showed gradual declines with advancing age (r = -0.44, P less than 0.005). In MID patients there were significant decreases in flow values with advancing age (r = -0.43, P less than 0.05), but flow values were consistently lower than in age-matched normals. Reductions of flow were most evident in the distribution of both middle cerebral arteries. Unlike MID patients, patients with SDAT had diffusely reduced flow values over all age ranges without correlation with advancing age. Reductions of mean flow values in both dementia groups were significantly correlated with severity of dementia (P less than 0.05 for both groups). Cerebral blood flow reductions related to the aging process also contribute to decreased cerebral perfusion in patients with MID. This is not true in SDAT, where the disease process itself pre-empts cerebral blood flow reductions attributable to aging.