Systemic amyloid deposition in old age and dementia of Alzheimer type: the relationship of brain amyloid to other amyloid

Summary We investigated amyloid deposition in the brain and other organs in 105 consecutive autopsy cases, aged 59 to 101 years. They consisted of two groups; 15 patients with dementia of Alzheimer type (DAT) and 90 patients without DAT. Amyloid deposition was found in 93% of all cases. The incidence of amyloid deposition increased with age. The number of organs affected with amyloid deposition in each case also increased with age. The incidence of amyloid deposition in each organ was as follows; 88% in pituitary gland, 66% in brain [amyloid of senile plaque (SP) (61%) and/or cerebral amyloid angiopathy (CAA) (56%)], 33% in pancreas, 3% in heart, and less in others. In immunohistochemical studies using the antisera to the various kinds of amyloid or related proteins, amyloid protein was demonstrated in brain amyloids including SP and CAA, but not in others. Cardiac amyloid was positive for prealbumin. Pituitary amyloid and CAA were positive for amyloid P-component. The incidence of brain amyloids in DAT were significantly higher than that in non-DAT. There was no significant difference in the incidence of pituitary and pancreatic amyloid between DAT and non-DAT. In the non-DAT patients, there were significant positive correlations in amyloid deposition between the brain and pituitary gland and between the brain and pancreas. Acceleration of amyloid deposition would be a process confined to the brain in the patients with DAT. The pathogenesis of the accelerated deposition of brain amyloids is discussed from the point of view of amyloidosis.Supported in part by the Research Committee on Primary Amyloidosis, Ministry of Health and Welfare, Japan     

β淀粉样蛋白与生长因子变化与老年性痴呆致病因素的研究

目的：检测血清β淀粉样蛋白（β－ＡＰ）和多肽生长因子含量变化,探讨其在Ａｌｚｈｅｉｍｅｒ病（ＡＤ）和血管性痴呆（ＶＤ）发病机制中的可能作用。方法：采用放射免疫分析法（ＲＩＡ）检测临床诊断为ＡＤ患者８例,ＶＤ患者１５例及６３例缺血性脑血管病（ＩＣＶＤ）患者血清β－ＡＰ、转化生长因子α（ＴＧＦ－α）和类胰岛素样生长因子Ⅱ（ＩＧＦ－Ⅱ）的水平,同时与健康对照组比较。结果：ＡＤ与ＶＤ患者β－ＡＰ、ＴＧＦ－α和ＩＧＦ－Ⅱ水平明显高于ＩＣＶＤ组和健康对照组,均具有显著性差异。ＩＣＶＤ患者血清β－ＡＰ、ＴＧＦ－α和 ＩＧＦ－Ⅱ水平亦明显高于对照组,其中以脑梗塞后遗症（ＳＣＩ）和椎基底动脉供血不足（ＶＢＩ）组增高十分明显,与对照组比较差异显著（Ｐ＜０．０５）。ＡＤ与 ＶＤ患者 ３项测定指标之间具有明显的正相关。结论：①β－ＡＰ可能是ＡＤ和ＶＤ发病的危险因素。②引起ＡＤ和ＶＤ神经元毒性作用进而导致痴呆．这可能与ＴＧＦ－α和ＩＧＦ－Ⅱ增多有关。③β－ＡＰ与ＴＧＦ－α、ＩＧＦ－Ⅱ密切相关,在老年斑形成过程中可能起重要作用。     

TRH stimulation test in dementia of the Alzheimer type and elderly controls

Dementia of the Alzheimer type (DAT) is known to be a heterogeneous syndrome with many clinical manifestations, including depression. In the present study, the thyrotropin-releasing hormone (TRH) stimulation test, previously used as a possible biological marker of depression, was administered to 15 DAT patients and 10 elderly controls. Seven out of 15 (47%) of the patients but none of the controls showed a blunted response with maximal changes of thyroid-stimulating hormone (TSH) from baseline of less than or equal to 7 microIU/ml following injection of 500 micrograms of TRH. The degree of blunting did not correlate with concurrent depression ratings.     

多梗塞性痴呆和Alzheimer型痴呆的SPECT和MRI比较研究

对２２例多梗塞性痴呆，１５例Ａｌｚｈｅｉｍｅｒ型痴呆病人和２４例同龄，同利手健康对照组作了单光子发射计算机断层显角和磁共振成象检查。结果发现ＳＰＥＣＴ在ＭＩＤ病人主要表现为多发性，局灶性脑放射性减低，两侧不对称，以额皮质，皮质下明显；ＤＡＴ病人主要表现为大脑皮质放射性对称性降低，以颞顶枕明显。     

Platelet phenolsulphotransferase activity in patients with dementia of Alzheimer type

Human blood platelets are more and more regarded as a reliable model of nerve cells, and some biochemical alterations found in platelet enzyme activities and receptor binding parameters may be related to analogous changes occuring in the central nervous system. Platelet phenol-sulphotransferase activity has been evaluated in some neurological disorders, such as Parkinson's disease and headache. In the present work we determined phenolsulphotransferase activity in platelets of 36 patients with dementia of Alzheimer type, and compared such activity values with those of 36 sex- and age-matched healthy controls. Patients showed a significantly higher platelet phenolsulphotransferase activity than control subjects, both with dopamine and with phenol as substrates. Moreover, a significant positive correlation was found between platelet enzyme activity and severity of illness. These findings are discussed in terms of the biochemical abnormalities found in the central nervous system of demented subjects, and in terms of the possible pathogenetic involvement of an altered phenolsulphotransferase activity (and, in general, of a modified monoamine metabolism) in such derangements of biochemical systems often occuring in dementia of Alzheimer type.     

Prevalence of moderate and severe Alzheimer dementia and multi-infarct dementia in the population of southeastern Sicily

We have calculate the prevalence rates of moderate and severe dementia of the Alzheimer type (DAT) and of multi-infarct dementia (MID) in a Sicilian population sample aged 40 and over. For DAT the prevalence rate is 0.80% among the over 40s and 2.42% among the over 65s. The prevalence rates for both types, but especially for DAT, increase higher prevalence of primary degenerative dementia among females.

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Sommario Abbiamo calcolato i tassi di prevalenza della demenza tipo Alzheimer e della demenza multiinfartuale di grado moderato e severo in un campione di popolazione siciliana di 40 anni ed oltre (4337 individui). Per la DAT il tasso di prevalenza è dello 0,80% [LF al 95% 0,56–1,11] nella popolazione di 40 anni ed oltre e diventa pari al 2,42% [LF al 95% 1,69–3,37] nella popolazione che ha raggiunto e superato il 65esimo anno di età.Per la MID la prevalenza è di 0,34% [LF al 95% 0,19–0,56] nella popolazione di 40 anni ed oltre, mentre nella popolazione di 65 anni ed oltre la prevalenza è dello 0,95% [LF al 95% 0,50–1,62].La prevalenza dei due tipi di demenza, e per quella tipo Alzheimer in particolare, aumenta significativamente con l'età. Altrettanto significativa è, sempre per la demenza degenerativa primaria, la più elevata prevalenza nel sesso femminile.

     

Ideomotor apraxia in patients with dementia of alzheimer type

Summary Ideomotor apraxia was checked in a carefully selected group of patients with Alzheimer's dementia, all in the mild stage of the disease. It was shown that ideomotor apraxia is not an early neuropsychological feature. When compared with other cognitive measures, the speed of deterioration of ideomotor apraxia appears to be particularly slow.Study supported by grant from the Consiglio Nazionale delle Ricerche (No. 8001829). Preliminary data presented at the XXIV Annual Meeting of the Italian Neurological Society (Pisa, October 1985)     

Integrity of the blood-CSF barrier in dementia of Alzheimer type: CSF/serum ratios of albumin and IgG

Summary Serum and cerebrospinal fluid (CSF) from 25 patients with dementia of Alzheimer type (DAT) and 25 controls were assayed for concentrations of albumin and IgG. The severity of dementia was rated with the Mini Mental State Examination. The CSF/serum ratio for albumin and IgG as well as the IgG index were used to evaluate blood-CSF barrier function in the respective groups. The control group was matched for age, sex and the indirect alcohol parameters, mean corpuscular volume and gamma-glutamyltranspeptidase. There were no signs of dysfunction of the blood-CSF barrier for proteins or signs of local synthesis of IgG in the central nervous system (CNS) of the demented patients. The permeability of the blood-CSF barrier appeared to be unrelated to dementia severity. The data do not support the hypothesis that a pathological leakage through the blood-CSF barrier facilitates the entry of extraneuronal proteins to the CNS, which might contribute to the pathophysiological process in DAT.     

Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type?

Summary Global cerebral blood flow, oxidative brain metabolism, and the cerebral arteriovenous differences of amino acids and ammonia were studied in 20 clinically diagnosed patients with early-onset dementia of Alzheimer type (DAT). Eleven healthy age-matched subjects and 15 healthy young volunteers served as controls. The most prominent abnormality in patients with early-onset DAT was a 44% reduction in the cerebral metabolic rate of glucose and a fourfold increase of lactate production, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were found not to be altered. The cerebral amino-N balance substantially changed in patients with early-onset DAT, showing a massive loss of amino acids and ammonia from the brain, which was indicative of excess protein catabolism due to cell degeneration in the acutely diseased brain. The abnormality found in glucose metabolism may suggest a perturbed control of glycolytic breakdown of glucose and its first oxidation step at the pyruvate dehydrogenase complex level, this thus being of pivotal significance in early-onset DAT.     

Reduced cholinesterase activity and somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with dementia of the Alzheimer type

Cholinesterase (ChE) activity and somatostatin-like immunoreactivity (SLI) of the cerebrospinal fluid were determined for 59 patients with dementia of the Alzheimer type (AD/SDAT) and for 19 age-matched control patients with no signs of dementia. Both ChE activities and SLI concentrations of cerebrospinal fluid were reduced significantly in dementia patients compared to the controls. In the AD/SDAT patients cholinesterase and somatostatin-like immunoreactivity levels seemed to be correlated with the severity of dementia. These findings agree with observations of reduced cortical acetylcholinesterase activities and somatostatin values in dementia of the Alzheimer type.     

Personality change in dementia of the Alzheimer type

Although cognitive impairment is the predominant feature of dementia, personality changes are also frequently reported. This study aimed to describe the nature of personality change in dementia of the Alzheimer type (DAT) and the relationship of this change to cognitive decline. An informant-based instrument was developed based on a personality inventory designed by Lewis Goldberg for measuring personality in the normal population. Twenty-eight clinicians used this inventory to rate the difference between people suffering from DAT and normal elderly people. Differences were found in all five factors of personality, with Conscientiousness and Intellect showing the most difference and Agreeableness showing the least difference. Based on the findings of this first study, a smaller questionnaire of 46 traits was developed. This was completed by 50 relatives of DAT patients, 50 relatives of controls and 167 carers of dementia sufferers recruited from Alzheimer’s Association support groups. Principal components analysis revealed a large factor which accounted for 33% of the variance suggesting a global change in personality. Rotation revealed three meaningful factors. Two of these factors were highly correlated to cognitive decline while the third showed only a moderate correlation. The significance of these results is discussed.     

CSF monoamine metabolites in dementia of the Alzheimer type and controls: Evidence for lower levels of homovanillic acid and 5-hydroxyindoleacetic acid in patients

The monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) were measured in 15 patients with dementia of the Alzheimer type (DAT) and 48 controls by means of a sensitive liquid chromotagraphic method. Relative to a large group of control subjects, the mean CSF 5-HIAA and HVA levels in patients with DAT appeared to be significantly lower. This finding appeared to be sex-related, in that the decrease in CSF monoamine metabolite levels could be attributed predominantly to male patients. A statistically significant relationship was found between 5-HIAA and HVA in both patients and controls. Linear regression analysis revealed a statistically significant positive relationship between age and CSF HVA in female controls only. No relationship was found between 5-HIAA and age either in patients or in controls. It is concluded that CSF 5-HIAA and HVA levels are decreased in male patients with DAT, probably signalling a sex-related change in serotonin and probably dopamine functioning in the central nervous system.     

Senile dementia of the Alzheimer type in the lundby study

Summary In spite of the great impact of senile dementia of the Alzheimer type (SDAT) on society, far too little is known about its epidemiology. In this study of a total, normal population from a geographically delimited area in Sweden, Lundby, 2612 persons were examined in 1957 by one psychiatrist (Hagnell). In 1972 the same population was reexamined irrespective of domicile. The incidence and risk of contracting SDAT during the 15 years were calculated. No cases of SDAT were diagnosed before the age of 60 years. The lifetime risk was for men 25.7% and for women 26.2%. When only the very severely impaired were taken into account, the figures were 14.5% in men and 14.6% in women.This study has been supported by the following grants: The Bank of Sweden Tercentenary Foundation No. 71/2; The Swedish Medical Research Council Nos. 3474, 4803, 6008, 6881; The Swedish Ministry of Health and Social Affairs, Delegation for Social Research No. 83/64:1–2.The study has been performed with approval of the Ethical Committee of the Lund University Faculty of Medicine and with the permission of the Swedish Data Inspection Board.     

Ten year cumulative incidence of dementia after late onset epilepsy of unknown etiology

Recent epidemiological studies suggest late life onset epilepsy of unknown etiology (LOEU) is a risk factor for future dementia. These studies rely on inclusion and exclusion of multiple diagnostic codes rather than structured data and neuroimaging findings, and thus challenging to interpret clinically. We assessed the cumulative incidence of dementia in patients with LOEU diagnosed through admission data and neuroimaging over a 10-year follow-up and compared baseline characteristics that distinguish group level incident dementia. We screened our hospital records for patients aged 55–69 with new epilepsy, admitted between 2000 and 2008, and excluded patients diagnosed with epilepsy from an underlying cause on medical records or neuroimaging. We used retrospective hospital data to follow patients for incident dementia or mortality at 10 years and compared baseline (demographics, depression or anxiety, vascular risk factors, results of electroencephalogram (EEG) studies, antidepressant use and type of ant seizure medication) and follow up (seizure recurrence, incident cerebrovascular disease) characteristics for patients with and without incident dementia.Fifty-four LOEU cases were screened, age at first seizure was 61 ± 5. The 10-year cumulative incidence of dementia was 22.20% (95% Confidence Interval 22.08–23.10%) and time to dementia diagnosis was 5.4 ± 3.9 years. Patients with incident dementia were more likely to be women (83% vs 38%, p = 0.002), have interictal epileptic form discharges (IED) on baseline EEG (70% vs 29%, p = 0.011) and depression or anxiety (50% vs 18%, p = 0.026). No differences were found in other baseline or follow up characteristics. Our results support recent findings of dementia incidence in LOEU. Prospective studies on LOEU should evaluate phenotypic determinants of individuals with late life epilepsy and the rate of progression to dementia.     

The Comprehensive Psychopathological Rating Scale in patients with dementia of Alzheimer type and multiinfarct dementia

ABSTRACT– Eighteen patients with the clinical diagnosis dementia of Alzheimer type (AD/SDAT) and 20 patients with the clinical diagnosis multiinfarct dementia (MID) were interviewed using a subscale to the Comprehensive Psychopathological Rating Scale (CPRS), consisting of items measuring psychopathological symptoms and signs commonly seen in patients with dementia. The aim of the investigation was to evaluate whether a difference in psychopathology between AD/SDAT and MID could be observed during a semistructured psychiatric interview using the CPRS. In both groups the duration of illness was similar and the dementia mild to moderate. All patients were subjected to somatic, psychiatric, laboratory, neurophysiologic and neuroradiologic examinations in order to obtain the correct clinical diagnoses. The results show that patients with AD/SDAT have a more variable psychopathology than patients with MID. Patients with MID were rated lower on all items used, especially those concerning verbal and personal contact. This might explain the generally accepted opinion that patients with MID have better contact with their surroundings and better preservation of their personality, even though they have the same degree of dementia as patients with AD/SDAT.     

CT study in senile dementia of Alzheimer type

We evaluated 14 patients with senile dementia of Alzheimer type (SDAT) and 15 age-matched normal elderly controls using psychological test and computed tomography scans. The low-density rate (LDR) was used as an index of brain atrophy. SDAT patients had significantly higher scores on the Hasegawa Dementia Scale (p< 0.01) and significantly lower scores on the Bender Gestalt Test (p<0.01) than control subjects. The LDRs of the left and right hemispheres were significantly higher in the SDAT group than in the control group in all three slices investigated (p<0.05/6 = 0.0083). In SDAT patients, significant diagnosis by hemisphere interaction was observed in one slice (p<0.05), with higher LDR on the left than on the right (p<0.05/6 = 0.0083). Our findings suggest that cortical atrophy is predominant on the left side in patients with SDAT.     

Cerebral perfusion patterns in vascular dementia of Binswanger type compared with senile dementia of Alzheimer type: a SPECT study

Summary Cerebral perfusion patterns in 18 cases with vascular dementia of Binswanger type (VDBT) (8 moderate and 10 severe cases) were compared with 25 cases with senile dementia of Alzheimer type (SDAT) (16 moderate and 9 severe cases) and 14 controls by single photon emission computed tomography usingN-isopropyl-p-¹²³I iodoamphetamine (IMP) as a tracer. The cerebral: cerebellar IMP uptake ratio (%) (CCR) was used as a measure of relative cerebral perfusion. The CCRs were about 85–90% in all areas in controls. Moderate VDBT patients showed a remarkable decrease of CCRs in the basal grey region (thalamus and basal ganglia) (right 79%, left 77%) and in the frontal area (right 79%, left 80%) (P<0.01). In severe VDBT patients a significant decrease of the CCR was noted in all regions (P<0.01). The decrease of mean CCRs in the hemispheres was significantly correlated with the severity of disease determined by psychometric testing. Patients with SDAT showed a significant decrease of the CCR in the parietal (right 71%, left 74%) and right temporal (78%) areas in the moderate stage (P<0.01), and further progression of dementia was associated with low perfusion areas extending to the frontal areas (78%,P<0.01). These differences in the perfusion patterns and their changes with progression of the illnesses may be reflected in characteristic clinical features.     

Apolipoprotein E in patients with dementia of the Alzheimer type and vascular dementia

The phenotypes of apolioprotein E (ApoE) in the plasma of patients with dementia of the Alzheimer type (DAT) and vascular dementia (VD) were determined by the isoelectric focusing method. The ApoE mRNA level in the skin fibroblasts was also determined by the Northern blot analysis. As compared with the control subjects, the frequency of the ApoE ε4 allele was significantly higher in the DAT group as well as the VD group, but was not significantly different in the cerebrovascular disease without dementia (CVD) group. The skin fibroblast ApoE mRNA level in the DAT group and the VD group was significantly lower than that in the control group. These findings suggest that the phenotype of ApoE is associated with DAT and VD, and that the lower level of ApoE mRNA may play an important role in the development of DAT as well as VD.     

Correlation between cognitive brain function and electrical brain activity in dementia of Alzheimer type

Summary Psychometric tests which assess cognitive brain function in dementia disorders are partly prone to artifacts, e.g., the experience of the investigator and the cooperation of the patient influences the results. An objective way to assess the degree of cognitive disturbance could be to measure neuronal activity represented by the electrical brain activity. The aim of the present study was to investigate how well cognitive function in dementia assessed by psychometric tests correlates with electrical brain activity (EEG). Multichannel EEG data was reduced into 3-D intracerebral equivalent dipole EEG generators allowing a more convenient statistical data management and valid physiological data interpretation. 35 patients suffering from dementia of Alzheimer type were investigated. An increase of dipole strength in the slow frequency bands, a more anterior equivalent dipole of alpha- and beta-activity, and a slowing of the EEG with increasing cognitive deterioration could be demonstrated. The results support the hypothesis that the amount of disturbance of cognitive function in dementia can be assessed by measuring the electrical activity of the brain.     

Variability of senile dementia of Alzheimer type: A clinicopathological viewpoint

Senile dementia of Alzheimer type (SDAT) is a hetero-genous entity and can be grouped into different categories based on clinicopathological characteristics. Although the presence of senile plaques, neurofibrillary tangles and neuronal loss throughout the cerebral cortices plays an important role in the development of SDAT, the presence of these structures is not essential. Sociopsychological factors should also be considered as important factors in the development of SDAT in subjects over 80 years of age.